It was in the 1980s that research on somatostatin(SST)in Alzheimer’s disease(AD)truly gained traction,demonstrating consistent colocalization with amyloid-β(Aβ),along with massive SST/SST cell losses(Almeida,2024)....It was in the 1980s that research on somatostatin(SST)in Alzheimer’s disease(AD)truly gained traction,demonstrating consistent colocalization with amyloid-β(Aβ),along with massive SST/SST cell losses(Almeida,2024).Although the field already had some grasp over the neuroendocrine and hypothalamic functions of the peptide,very little was known about the GABAergic interneurons(SST-INs)that synthesize it in cortical/hippocampal regions.Quite excitingly,over 40 years later,research has grown effervescent.展开更多
Striatal interneurons play a key role in modulating striatal-dependent behaviors,including motor activity and reward and emotional processing.Interneurons not only provide modulation to the basal ganglia circuitry und...Striatal interneurons play a key role in modulating striatal-dependent behaviors,including motor activity and reward and emotional processing.Interneurons not only provide modulation to the basal ganglia circuitry under homeostasis but are also involved in changes to plasticity and adaptation during disease conditions such as Parkinson's or Huntington's disease.This review aims to summarize recent findings regarding the role of striatal cholinergic and GABAergic interneurons in providing circuit modulation to the basal ganglia in both homeostatic and disease conditions.In addition to direct circuit modulation,striatal interneurons have also been shown to provide trophic support to maintain neuron populations in adulthood.We discuss this interesting and novel role of striatal interneurons,with a focus on the maintenance of adult dopaminergic neurons from interneuronderived sonic-hedgehog.展开更多
Chx10-expressing V2 a(Chx10+V2 a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2 a interneurons in the re...Chx10-expressing V2 a(Chx10+V2 a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2 a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2 a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2 a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2 a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2 a interneurons also play an important role in rhythmic patterning maintenance, leftright alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2 a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2 a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2 a interneurons transplanted in spinal cord injury foci.展开更多
Dear Editor,The perirhinal cortex (PER) is conceptually important in the recognition memory, especially in familiarity discrimination, whereas the hippocampus is important for association and recollection [1]. This no...Dear Editor,The perirhinal cortex (PER) is conceptually important in the recognition memory, especially in familiarity discrimination, whereas the hippocampus is important for association and recollection [1]. This notion is known as the dualprocess model of recognition memory.展开更多
CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP o...CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.展开更多
Spinal cord injury（SCI）with consecutive paralysis below the lesion level is a severe disorder affecting the patient for the rest of his or her life.So far,there is no known fundamental intervention strategy for effi...Spinal cord injury（SCI）with consecutive paralysis below the lesion level is a severe disorder affecting the patient for the rest of his or her life.So far,there is no known fundamental intervention strategy for efficiently helping those patients regain their motor abilities,despite intense research in this area.Thus,effective treatment for those patients is still an open question. A spinal cord injury is accompanied by a prima- ry, severe and irreversible neuronal cell death in the trauma region, fol- lowed by a secondary extensive cell necrosis in the lesion surrounding areas. Nevertheless, recent studies indicate that regeneration after spinal cord injury could be possible if three substantial steps are fulfilled： （1） reduction of the inhibitory environment at the SCI lesion site, （2） iden- tification of a neural substrate to establish new spinal circuits, and （3） support of these circuits to form permanent, functional motor, sensory, or autonomic connections （Dru and Hoh, 2015）.展开更多
OBJECTIVE Cognitive dysfunc⁃tion is a core disturbance of schizophrenia,appear to emerge from impaired neural activity.The anterior cingulate cortex(ACC)is an integra⁃tion hub for higher-order thalamic inputs impor⁃ta...OBJECTIVE Cognitive dysfunc⁃tion is a core disturbance of schizophrenia,appear to emerge from impaired neural activity.The anterior cingulate cortex(ACC)is an integra⁃tion hub for higher-order thalamic inputs impor⁃tant for complex cognitive tasks such as learning and memory processes,attention and social interaction.Parvalbumin(PV)interneurons could filter information at pyramidal neurons of ACC,and the abnormal PV interneurons have been observed in both humans and animal models of schizophrenia.However,the mechanisms of PV interneurons in ACC regulating cognition in schizophrenia is poorly understood.METHODS The pregnant mice were injected with methyl⁃azoxymethanol acetate(MAM)on gestational day(GD)16 for the neurodevelopmental MAM model of schizophrenia in our study.We investi⁃gated the cognitive behaviors by a serious of tests such as pre-pulse inhibition,Y maze,novel object and novel location recognition and the intrinsic excitability of PV interneurons and inhibi⁃tory synaptic transmission onto pyramidal cells localized in layer 5 of ACC by whole-cell record⁃ings.Further,the PV interneurons were regulat⁃ed by designer receptor exclusively activated by a designer drug(DREADD)system and the D-serine,a co-agonist of N-methyl-D-aspartate(NMDA)receptors.RESULTS①MAM mice showed the cognitive deficits and hypo-excitability of PV interneurons in ACC.②Restoration of PV interneuron activity in ACC improved cognitive function in MAM mice.③Inhibition of PV interneu⁃ron activity in ACC was sufficient to cause cogni⁃tive dysfunction in control mice.④NMDA recep⁃tors of PV interneurons in ACC were impaired in MAM mice.⑤Deficits of NMDA receptor sig⁃naling specifically in PV interneurons and of cog⁃nitive behaviors in MAM mice were rescued by D-serine.CONCLUSION PV interneurons in ACC are closely related to cognitive function in the MAM model of schizophrenia and D-serine maybe a potential therapy for schizophrenia.展开更多
Author present the interplay between different neuron types in the spontaneous electrical activity of low density cortical in vitro networks grown on MEA （multielectrode arrays） of glass neurochips. In 10% of the ne...Author present the interplay between different neuron types in the spontaneous electrical activity of low density cortical in vitro networks grown on MEA （multielectrode arrays） of glass neurochips. In 10% of the networks, the continuously spiking activity of some neurons was inhibited by synchronous bursts or superbursts of the majority of the other neurons. Immunohistochemical staining subsequent to MEA recordings suggest that the synchronously bursting neurons are parvalbumin-positive interneurons with abundant axonal ramifications. Blocking chemical synaptic transmission by Ca2＋-free medium revealed that the curbed spiking neurons are intrinsically active. It is assumed that these neurons are pyramidal cells which may be inhibited by groups of synchronously bursting interneurons. It is propose that the observed burst-induced inhibition is an important principle in the temporal organization of neuronal activity as well as in the restriction of excitation, and thus essential for information processing in the cerebral cortex.展开更多
Gamma-amino-butyric acid（GABA）-containing interneurons are crucial to both development and function of the brain. Down-regulation of GABAergic inhibition may result in the generation of epileptiform activity. Loss, ...Gamma-amino-butyric acid（GABA）-containing interneurons are crucial to both development and function of the brain. Down-regulation of GABAergic inhibition may result in the generation of epileptiform activity. Loss, axonal sprouting, and dysfunction of interneurons are regarded as mechanisms involved in epileptogenesis. Recent evidence suggests that network connectivity and the properties of interneurons are responsible for excitatory-inhibitory neuronal circuits. The balance between excitation and inhibition in CA1 neuronal circuitry is considerably altered during epileptic changes. This review discusses interneuron diversity, the causes of interneuron dysfunction in epilepsy, and the possibility of using GABAergic neuronal progenitors for the treatment of epilepsy.展开更多
While the hippocampus has been implicated in supporting the association among time-separated events,the underlying cellular mechanisms have not been fully clarified.Here,we combined in vivo multi-channel recording and...While the hippocampus has been implicated in supporting the association among time-separated events,the underlying cellular mechanisms have not been fully clarified.Here,we combined in vivo multi-channel recording and optogenetics to investigate the activity of hippocampal interneurons in freely-moving mice performing a trace eyeblink conditioning(tEBC)task.We found that the hippocampal interneurons exhibited conditioned stimulus(CS)-evoked sustained activity,which predicted the performance of conditioned eyeblink responses(CRs)in the early acquisition of the tEBC.Consistent with this,greater proportions of hippocampal pyramidal cells showed CS-evoked decreased activity in the early acquisition of the tEBC.Moreover,optogenetic suppression of the sustained activity in hippocampal interneurons severely impaired acquisition of the tEBC.In contrast,suppression of the sustained activity of hippocampal interneurons had no effect on the performance of well-learned CRs.Our findings highlight the role of hippocampal interneurons in the tEBC,and point to a potential cellular mechanism subserving associative learning.展开更多
Inhibitory GABAergic interneurons are fundamental elements of cortical circuits and play critical roles in shaping network activity. Dysfunction of interneurons can lead to various brain disorders, including epilepsy,...Inhibitory GABAergic interneurons are fundamental elements of cortical circuits and play critical roles in shaping network activity. Dysfunction of interneurons can lead to various brain disorders, including epilepsy,schizophrenia, and anxiety. Based on the electrophysiological properties, cell morphology, and molecular identity,interneurons could be classified into various subgroups. In this study, we investigated the density and laminar distribution of different interneuron types and the coexpression of molecular markers in epileptic human cortex.We found that parvalbumin(PV) and somatostatin(SST)neurons were distributed in all cortical layers except layer I, while tyrosine hydroxylase(TH) and neuropeptide Y(NPY) were abundant in the deep layers and white matter.Cholecystokinin(CCK) neurons showed a high density in layers IV and VI. Neurons with these markers constituted*7.2%(PV), 2.6%(SST), 0.5%(TH), 0.5%(NPY), and4.4%(CCK) of the gray-matter neuron population. Doubleand triple-labeling revealed that NPY neurons were also SST-immunoreactive(97.7%), and TH neurons were more likely to express SST(34.2%) than PV(14.6%). A subpopulation of CCK neurons(28.0%) also expressed PV, but none contained SST. Together, these results revealed the density and distribution patterns of different interneuron populations and the overlap between molecular markers in epileptic human cortex.展开更多
Neuronal oscillations are fundamental to hip- pocampal function. It has been shown that GABAergic interneurons make an important contribution to hippocampal oscillations, but the underlying mechanism is not well under...Neuronal oscillations are fundamental to hip- pocampal function. It has been shown that GABAergic interneurons make an important contribution to hippocampal oscillations, but the underlying mechanism is not well understood. Here, using whole-cell recording in the complete hippocampal formation isolated from rats at postnatal days 14-18, we showed that GABAA receptormediated activity enhanced the generation of slow CA1 oscillations. In vitro, slow oscillations （0.5-1.5 Hz） were generated in CA1 neurons, and they consisted primarily of excitatory rather than inhibitory membrane-potential changes. These oscillations were greatly reduced by blocking GABAA receptor-mediated activity with bicuculline and were enhanced by increasing such activity with midazolam, suggesting that interneurons are required for oscillation generation. Consistently, CA1 fast-spiking interneurons were found to generate action potentials usually preceding those in CA1 pyramidal cells. These findings indicate a GABAA receptor-based mechanism for the generation of the slow CA1 oscillation in the hippocampus.展开更多
Neuroligins(NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal mod...Neuroligins(NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal model studies, and affect synaptic connections and synaptic plasticity in several brain regions. Yet current research mainly focuses on pyramidal neurons, while the function of NLs in interneurons remains to be understood. To explore the functional difference among NLs in the subtypespecific synapse formation of both pyramidal neurons and interneurons, we performed viral-mediated shRNA knockdown of NLs in cultured rat cortical neurons and examined the synapses in the two major types of neurons. Our results showed that in both types of neurons, NL1 and NL3 were involved in excitatory synapse formation, and NL2 in GABAergic synapse formation. Interestingly, NL1 affectedGABAergic synapse formation more specifically than NL3,and NL2 affected excitatory synapse density preferentially in pyramidal neurons. In summary, our results demonstrated that different NLs play distinct roles in regulating the development and balance of excitatory and inhibitory synapses in pyramidal neurons and interneurons.展开更多
The caudal forelimb area(CFA)of the mouse cortex is essential in many forelimb movements,and diverse types of GABAergic interneuron in the CFA are distinct in the mediation of cortical inhibition in motor information ...The caudal forelimb area(CFA)of the mouse cortex is essential in many forelimb movements,and diverse types of GABAergic interneuron in the CFA are distinct in the mediation of cortical inhibition in motor information processing.However,their long-range inputs remain unclear.In the present study,we combined the monosynaptic rabies virus system with Cre driver mouse lines to generate a whole-brain map of the inputs to three major inhibitory interneuron types in the CFA.We discovered that each type was innervated by the same upstream areas,but there were quantitative differences in the inputs from the cortex,thalamus,and pallidum.Comparing the locations of the interneurons in two subregions of the CFA,we discovered that their long-range inputs were remarkably different in distribution and proportion.This whole-brain mapping indicates the existence of parallel pathway organization in the forelimb subnetwork and provides insight into the inhibitory processes in forelimb movement to reveal the structural architecture underlying the functions of the CFA.展开更多
OBJECTIVE To explore the changes of calretinin interneurons in APP/PS1 mouse model and their correlation with the pathological features of Alzheimer disease.METHODS The morphological differences between the brain regi...OBJECTIVE To explore the changes of calretinin interneurons in APP/PS1 mouse model and their correlation with the pathological features of Alzheimer disease.METHODS The morphological differences between the brain regions of control and transgenic(TG) mice were detected by Nissl staining.By immunofluorescence histochemistry and western blotting,the expression of related proteins was detected,including GAD65/67,calretinin and Aβ1-42.At the same time,in terms of behavioral experiments,the motor ability,the level of fear and cognitive level of control and transgenic mice were tested through open-field test,elevated plus maze and novel object recognition(NOR) experiment.RESULTS According to Nissl staining results,compared with the control group,the number of cells in glomerular layer(GL) and granule cell layer(GCL) of olfactory bulb in the TG group was significantly reduced.Meanwhile,in the hippocampus,compared with the control group,the ventral CA1 and CA3 is dysplastic in APP/PS1 group.Moreover,the morphology of subgranular zone(SGZ) layer cells in the dorsal DG significantly changed and the number of cells in hilar regions significantly decreased in the TG group.Other brain regions associated with cognition,including the piriform cortex,entorhinal cortex and the prefrontal cortex,showed no significant changes between the control and TG group.By Western blotting experiment,compared with the control mice,it was found that the expression of GAD65/67 and calretinin in the olfactory bulb and hippocampus was significantly decreased in the TG group.In detail,the level of the protein in the relevant brain regions was detected by immunofluorescence histochemistry(IHC).The expression of calretinin in GL of the olfactory bulb and the hippocampal DG region was significantly decreased,which was correlated with the distribution of Aβ1-42 by IHC.In the part of functional behavioral experiment,compared with the control mice,the total distance of movement in 6 M TG group mice was significantly increased in the open field test.In the elevated plus maze test,there were no significant differences between control and TG group.In addition,the mice of TG group lacked the ability to distinguish between old and new objects in the NOR experiment.CONCLUSION The number of calretinin interneurons in olfactory bulb and hippocampus decreased significantly in APP/PS1 mouse model,which is more correlated with the distribution of Aβ1-42 and functional disorders,including the enhancement of spontaneous locomotor activity and cognitive impairment.展开更多
The inhibitory sources in the thalamic nuclei are local interneurons and neurons of the thalamic reticular nucleus. Studies of models of absence epilepsy have shown that the seizures are associated with an excess of i...The inhibitory sources in the thalamic nuclei are local interneurons and neurons of the thalamic reticular nucleus. Studies of models of absence epilepsy have shown that the seizures are associated with an excess of inhibitory neurotransmission in the thalamus. In the present study, we used light- microscopic gamma-aminobutyric acid （GABA） immunocytochemistry to quantify the interneurons in the lateral geniculate （LGN）, ventral posteromedial （VPM）, and ventral posterolateral （VPL） thalamic nuclei, and compared the values from normal Wistar rats and genetic absence epilepsy rats from Strasbourg （GAERS）. We found that in both Wistar rats and GAERS, the proportion of interneurons was significantly higher in the LGN than in the VPM and VPL. In the LGN of Wistar rats, 16.4% of the neurons were interneurons and in the GAERS, the value was 15.1%. In the VPM, the proportion of interneurons was 4.2% in Wistar and 14.9% in GAERS; in the VPL the values were 3.7% for Wistar and 11.1% for the GAERS. There was no significant difference between Wistar rats and the GAERS regarding the counts of interneurons in the LGN, whereas the VPM and VPL showed significantly higher counts in GAERS. Comparison of the mean areas of both relay cells and interneuronal profiles showed no significant differences between Wistar rats and GAERS. These findings show that in the VPL and the VPM there are relatively more GABAergic interneurons in GAERS than in Wistar rats. This may represent a compensatory response of the thalamocortical circuitry to the absence seizures or may be related to the production of absence seizures.展开更多
Autapses selectively form in specific cell types in many brain regions.Previous studies have also found putative autapses in principal spiny projection neurons(SPNs)in the striatum.However,it remains unclear whether t...Autapses selectively form in specific cell types in many brain regions.Previous studies have also found putative autapses in principal spiny projection neurons(SPNs)in the striatum.However,it remains unclear whether these neurons indeed form physiologically functional autapses.We applied whole-cell recording in striatal slices and identified autaptic cells by the occurrence of prolonged asynchronous release(AR)of neurotransmitters after bursts of high-frequency action potentials(APs).Surprisingly,we found no autaptic AR in SPNs,even in the presence of Sr^(2+).However,robust autaptic AR was recorded in parvalbumin(PV)-expressing neurons.The autaptic responses were mediated by GABA_(A) receptors and their strength was dependent on AP frequency and number.Further computer simulations suggest that autapses regulate spiking activity in PV cells by providing self-inhibition and thus shape network oscillations.Together,our results indicate that PV neurons,but not SPNs,form functional autapses,which may play important roles in striatal functions.展开更多
Tonotopy,the spatial organization of neurons based on their sound frequency responses,is a fundamental feature of the auditory pathway,extending from the cochlea to the auditory cortex.While excitatory neurons have be...Tonotopy,the spatial organization of neurons based on their sound frequency responses,is a fundamental feature of the auditory pathway,extending from the cochlea to the auditory cortex.While excitatory neurons have been considered necessary for tonotopy in the cortex,the role of inhibitory interneurons remains unclear.Using a novel two-channel widefield Ca~(2+)imaging system,the 2-Channel Alternating exposure wide-Field Explorer(2-CAFE),we simultaneously measured the sound responsiveness of distinct neuron types in awake mice.Combined with two-photon imaging,we observed that GABAergic interneurons followed a similar tonotopic organization to the conventional auditory maps at both mesoscale and single-cell resolutions.Among the major interneuron subtypes—parvalbumin(PV),somatostatin(SST),and vasoactive intestinal peptide(VIP)—PV interneurons demonstrated a critical role in maintaining tonotopy.Inactivation of PV neurons,but not VIP or SST neurons,significantly weakened the tonotopic strength in the auditory cortex.These findings establish PV interneurons as essential components of auditory cortical tonotopy.展开更多
Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsol...Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.展开更多
Background Alzheimer’s disease(AD)is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists.Neuroinflammation is central to the pathology progression,with evidence sugge...Background Alzheimer’s disease(AD)is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists.Neuroinflammation is central to the pathology progression,with evidence suggesting that microglia-released galectin-3(gal3)plays a pivotal role by amplifying neuroinflammation in AD.However,the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown.Methods Here,we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo(20-80 Hz)by performing electrophysiological recordings in the hippocampal CA3 area of wild-type(WT)mice and of the 5×FAD mouse model of AD.In addition,the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes,and amyloid-β(Aβ)plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout(KO).Results Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner,which was accompanied by impairment of cellular dynamics in fast-spiking interneurons(FSNs)and pyramidal cells.We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139,which also prevented Aβ42-induced degradation of gamma oscillations.Further-more,the 5×FAD mice lacking gal3(5×FAD-Gal3KO)exhibited WT-like gamma network dynamics and decreased Aβplaque load.Conclusions We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs,inducing a network performance collapse.Moreover,our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.展开更多
文摘It was in the 1980s that research on somatostatin(SST)in Alzheimer’s disease(AD)truly gained traction,demonstrating consistent colocalization with amyloid-β(Aβ),along with massive SST/SST cell losses(Almeida,2024).Although the field already had some grasp over the neuroendocrine and hypothalamic functions of the peptide,very little was known about the GABAergic interneurons(SST-INs)that synthesize it in cortical/hippocampal regions.Quite excitingly,over 40 years later,research has grown effervescent.
文摘Striatal interneurons play a key role in modulating striatal-dependent behaviors,including motor activity and reward and emotional processing.Interneurons not only provide modulation to the basal ganglia circuitry under homeostasis but are also involved in changes to plasticity and adaptation during disease conditions such as Parkinson's or Huntington's disease.This review aims to summarize recent findings regarding the role of striatal cholinergic and GABAergic interneurons in providing circuit modulation to the basal ganglia in both homeostatic and disease conditions.In addition to direct circuit modulation,striatal interneurons have also been shown to provide trophic support to maintain neuron populations in adulthood.We discuss this interesting and novel role of striatal interneurons,with a focus on the maintenance of adult dopaminergic neurons from interneuronderived sonic-hedgehog.
基金supported by the National Natural Science Foundation of China,No. 81870977 (to YW)the Natural Science Foundation of Heilongjiang Province of China,No. JQ2021H004 (to YW)+1 种基金PhD research foundation of Mudanjiang Medicine College,No. 2021-MYBSKY-039 (to WYL)Fundamental Research Funds for Heilongjiang Provincial Universities,No. 2021-KYYWF-0469 (to WYL)。
文摘Chx10-expressing V2 a(Chx10+V2 a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2 a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2 a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2 a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2 a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2 a interneurons also play an important role in rhythmic patterning maintenance, leftright alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2 a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2 a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2 a interneurons transplanted in spinal cord injury foci.
基金supported by grants from the Beijing Municipal Science & Technology Commission (Z181100001518001)the Interdisciplinary Research Funds of Beijing Normal University
文摘Dear Editor,The perirhinal cortex (PER) is conceptually important in the recognition memory, especially in familiarity discrimination, whereas the hippocampus is important for association and recollection [1]. This notion is known as the dualprocess model of recognition memory.
基金This work was supported by Science and Technology Innovation 2030-Major Project(2021ZD0203501)the National Natural Science Foundation of China(81930030,31771109,and 31722023)+5 种基金the National Key R&D Program of China(2019YFA0508603)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057)Project for Hangzhou Medical Disciplines of ExcellenceKey Project for Hangzhou Medical Disciplinesthe Fundamental Research Funds for the Central Universities of China(2018XZZX002-02,2019XZZX001-01-04,and 2019FZA7009)the National Postdoctoral Program for Innovative Talents(BX2021263).
文摘CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
基金supported by DFG Grant KFO 213 and the "ElseKr?ner-Fresenius-Stiftung" to JG
文摘Spinal cord injury（SCI）with consecutive paralysis below the lesion level is a severe disorder affecting the patient for the rest of his or her life.So far,there is no known fundamental intervention strategy for efficiently helping those patients regain their motor abilities,despite intense research in this area.Thus,effective treatment for those patients is still an open question. A spinal cord injury is accompanied by a prima- ry, severe and irreversible neuronal cell death in the trauma region, fol- lowed by a secondary extensive cell necrosis in the lesion surrounding areas. Nevertheless, recent studies indicate that regeneration after spinal cord injury could be possible if three substantial steps are fulfilled： （1） reduction of the inhibitory environment at the SCI lesion site, （2） iden- tification of a neural substrate to establish new spinal circuits, and （3） support of these circuits to form permanent, functional motor, sensory, or autonomic connections （Dru and Hoh, 2015）.
文摘OBJECTIVE Cognitive dysfunc⁃tion is a core disturbance of schizophrenia,appear to emerge from impaired neural activity.The anterior cingulate cortex(ACC)is an integra⁃tion hub for higher-order thalamic inputs impor⁃tant for complex cognitive tasks such as learning and memory processes,attention and social interaction.Parvalbumin(PV)interneurons could filter information at pyramidal neurons of ACC,and the abnormal PV interneurons have been observed in both humans and animal models of schizophrenia.However,the mechanisms of PV interneurons in ACC regulating cognition in schizophrenia is poorly understood.METHODS The pregnant mice were injected with methyl⁃azoxymethanol acetate(MAM)on gestational day(GD)16 for the neurodevelopmental MAM model of schizophrenia in our study.We investi⁃gated the cognitive behaviors by a serious of tests such as pre-pulse inhibition,Y maze,novel object and novel location recognition and the intrinsic excitability of PV interneurons and inhibi⁃tory synaptic transmission onto pyramidal cells localized in layer 5 of ACC by whole-cell record⁃ings.Further,the PV interneurons were regulat⁃ed by designer receptor exclusively activated by a designer drug(DREADD)system and the D-serine,a co-agonist of N-methyl-D-aspartate(NMDA)receptors.RESULTS①MAM mice showed the cognitive deficits and hypo-excitability of PV interneurons in ACC.②Restoration of PV interneuron activity in ACC improved cognitive function in MAM mice.③Inhibition of PV interneu⁃ron activity in ACC was sufficient to cause cogni⁃tive dysfunction in control mice.④NMDA recep⁃tors of PV interneurons in ACC were impaired in MAM mice.⑤Deficits of NMDA receptor sig⁃naling specifically in PV interneurons and of cog⁃nitive behaviors in MAM mice were rescued by D-serine.CONCLUSION PV interneurons in ACC are closely related to cognitive function in the MAM model of schizophrenia and D-serine maybe a potential therapy for schizophrenia.
文摘Author present the interplay between different neuron types in the spontaneous electrical activity of low density cortical in vitro networks grown on MEA （multielectrode arrays） of glass neurochips. In 10% of the networks, the continuously spiking activity of some neurons was inhibited by synchronous bursts or superbursts of the majority of the other neurons. Immunohistochemical staining subsequent to MEA recordings suggest that the synchronously bursting neurons are parvalbumin-positive interneurons with abundant axonal ramifications. Blocking chemical synaptic transmission by Ca2＋-free medium revealed that the curbed spiking neurons are intrinsically active. It is assumed that these neurons are pyramidal cells which may be inhibited by groups of synchronously bursting interneurons. It is propose that the observed burst-induced inhibition is an important principle in the temporal organization of neuronal activity as well as in the restriction of excitation, and thus essential for information processing in the cerebral cortex.
基金supported by the National Natural Science Foundation of China (81100970,81370737,and 81371422)
文摘Gamma-amino-butyric acid（GABA）-containing interneurons are crucial to both development and function of the brain. Down-regulation of GABAergic inhibition may result in the generation of epileptiform activity. Loss, axonal sprouting, and dysfunction of interneurons are regarded as mechanisms involved in epileptogenesis. Recent evidence suggests that network connectivity and the properties of interneurons are responsible for excitatory-inhibitory neuronal circuits. The balance between excitation and inhibition in CA1 neuronal circuitry is considerably altered during epileptic changes. This review discusses interneuron diversity, the causes of interneuron dysfunction in epilepsy, and the possibility of using GABAergic neuronal progenitors for the treatment of epilepsy.
基金the National Natural Science Foundation of China(32071014)the Open Project Program of Brain and Intelligence Research Key Laboratory of Chongqing Education Commission(BIR2019001)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(31921003).
文摘While the hippocampus has been implicated in supporting the association among time-separated events,the underlying cellular mechanisms have not been fully clarified.Here,we combined in vivo multi-channel recording and optogenetics to investigate the activity of hippocampal interneurons in freely-moving mice performing a trace eyeblink conditioning(tEBC)task.We found that the hippocampal interneurons exhibited conditioned stimulus(CS)-evoked sustained activity,which predicted the performance of conditioned eyeblink responses(CRs)in the early acquisition of the tEBC.Consistent with this,greater proportions of hippocampal pyramidal cells showed CS-evoked decreased activity in the early acquisition of the tEBC.Moreover,optogenetic suppression of the sustained activity in hippocampal interneurons severely impaired acquisition of the tEBC.In contrast,suppression of the sustained activity of hippocampal interneurons had no effect on the performance of well-learned CRs.Our findings highlight the role of hippocampal interneurons in the tEBC,and point to a potential cellular mechanism subserving associative learning.
基金supported by the National Natural Science Foundation of China (31430038 and 81571275)
文摘Inhibitory GABAergic interneurons are fundamental elements of cortical circuits and play critical roles in shaping network activity. Dysfunction of interneurons can lead to various brain disorders, including epilepsy,schizophrenia, and anxiety. Based on the electrophysiological properties, cell morphology, and molecular identity,interneurons could be classified into various subgroups. In this study, we investigated the density and laminar distribution of different interneuron types and the coexpression of molecular markers in epileptic human cortex.We found that parvalbumin(PV) and somatostatin(SST)neurons were distributed in all cortical layers except layer I, while tyrosine hydroxylase(TH) and neuropeptide Y(NPY) were abundant in the deep layers and white matter.Cholecystokinin(CCK) neurons showed a high density in layers IV and VI. Neurons with these markers constituted*7.2%(PV), 2.6%(SST), 0.5%(TH), 0.5%(NPY), and4.4%(CCK) of the gray-matter neuron population. Doubleand triple-labeling revealed that NPY neurons were also SST-immunoreactive(97.7%), and TH neurons were more likely to express SST(34.2%) than PV(14.6%). A subpopulation of CCK neurons(28.0%) also expressed PV, but none contained SST. Together, these results revealed the density and distribution patterns of different interneuron populations and the overlap between molecular markers in epileptic human cortex.
基金supported by grants from the National Natural Science Foundation of China(9113271130970960+2 种基金31471078)a Key Scientific Project of the Shanghai Science and Technology Commission,China(15JC1400102)the Shanghai Pu-Jiang Program,China(08PJ14044)
文摘Neuronal oscillations are fundamental to hip- pocampal function. It has been shown that GABAergic interneurons make an important contribution to hippocampal oscillations, but the underlying mechanism is not well understood. Here, using whole-cell recording in the complete hippocampal formation isolated from rats at postnatal days 14-18, we showed that GABAA receptormediated activity enhanced the generation of slow CA1 oscillations. In vitro, slow oscillations （0.5-1.5 Hz） were generated in CA1 neurons, and they consisted primarily of excitatory rather than inhibitory membrane-potential changes. These oscillations were greatly reduced by blocking GABAA receptor-mediated activity with bicuculline and were enhanced by increasing such activity with midazolam, suggesting that interneurons are required for oscillation generation. Consistently, CA1 fast-spiking interneurons were found to generate action potentials usually preceding those in CA1 pyramidal cells. These findings indicate a GABAA receptor-based mechanism for the generation of the slow CA1 oscillation in the hippocampus.
基金supported by grants from the National Natural Science Foundation of China(31571049 and81561168022)the National Basic Research Program of China(2015CB910801)+2 种基金Zhejiang Provincial Natural Science Foundation of China(LR19H090001 and LD19H090002)a joint grant from the National Natural Science Foundation of China and the Research Grants Council of Hong Kong,China(8151101104 and N_HKUST625/15)Fundamental Research Funds for the CentralUniversities of China
文摘Neuroligins(NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal model studies, and affect synaptic connections and synaptic plasticity in several brain regions. Yet current research mainly focuses on pyramidal neurons, while the function of NLs in interneurons remains to be understood. To explore the functional difference among NLs in the subtypespecific synapse formation of both pyramidal neurons and interneurons, we performed viral-mediated shRNA knockdown of NLs in cultured rat cortical neurons and examined the synapses in the two major types of neurons. Our results showed that in both types of neurons, NL1 and NL3 were involved in excitatory synapse formation, and NL2 in GABAergic synapse formation. Interestingly, NL1 affectedGABAergic synapse formation more specifically than NL3,and NL2 affected excitatory synapse density preferentially in pyramidal neurons. In summary, our results demonstrated that different NLs play distinct roles in regulating the development and balance of excitatory and inhibitory synapses in pyramidal neurons and interneurons.
基金supported by the National Natural Science Foundation of China(61721092,91749209,and 31871088)the Director Fund of Wuhan National Laboratory for Optoelectronics。
文摘The caudal forelimb area(CFA)of the mouse cortex is essential in many forelimb movements,and diverse types of GABAergic interneuron in the CFA are distinct in the mediation of cortical inhibition in motor information processing.However,their long-range inputs remain unclear.In the present study,we combined the monosynaptic rabies virus system with Cre driver mouse lines to generate a whole-brain map of the inputs to three major inhibitory interneuron types in the CFA.We discovered that each type was innervated by the same upstream areas,but there were quantitative differences in the inputs from the cortex,thalamus,and pallidum.Comparing the locations of the interneurons in two subregions of the CFA,we discovered that their long-range inputs were remarkably different in distribution and proportion.This whole-brain mapping indicates the existence of parallel pathway organization in the forelimb subnetwork and provides insight into the inhibitory processes in forelimb movement to reveal the structural architecture underlying the functions of the CFA.
基金CAMS Innovation Fund for Medical Sciences(CIFMS) (2016-I2M-1-004).
文摘OBJECTIVE To explore the changes of calretinin interneurons in APP/PS1 mouse model and their correlation with the pathological features of Alzheimer disease.METHODS The morphological differences between the brain regions of control and transgenic(TG) mice were detected by Nissl staining.By immunofluorescence histochemistry and western blotting,the expression of related proteins was detected,including GAD65/67,calretinin and Aβ1-42.At the same time,in terms of behavioral experiments,the motor ability,the level of fear and cognitive level of control and transgenic mice were tested through open-field test,elevated plus maze and novel object recognition(NOR) experiment.RESULTS According to Nissl staining results,compared with the control group,the number of cells in glomerular layer(GL) and granule cell layer(GCL) of olfactory bulb in the TG group was significantly reduced.Meanwhile,in the hippocampus,compared with the control group,the ventral CA1 and CA3 is dysplastic in APP/PS1 group.Moreover,the morphology of subgranular zone(SGZ) layer cells in the dorsal DG significantly changed and the number of cells in hilar regions significantly decreased in the TG group.Other brain regions associated with cognition,including the piriform cortex,entorhinal cortex and the prefrontal cortex,showed no significant changes between the control and TG group.By Western blotting experiment,compared with the control mice,it was found that the expression of GAD65/67 and calretinin in the olfactory bulb and hippocampus was significantly decreased in the TG group.In detail,the level of the protein in the relevant brain regions was detected by immunofluorescence histochemistry(IHC).The expression of calretinin in GL of the olfactory bulb and the hippocampal DG region was significantly decreased,which was correlated with the distribution of Aβ1-42 by IHC.In the part of functional behavioral experiment,compared with the control mice,the total distance of movement in 6 M TG group mice was significantly increased in the open field test.In the elevated plus maze test,there were no significant differences between control and TG group.In addition,the mice of TG group lacked the ability to distinguish between old and new objects in the NOR experiment.CONCLUSION The number of calretinin interneurons in olfactory bulb and hippocampus decreased significantly in APP/PS1 mouse model,which is more correlated with the distribution of Aβ1-42 and functional disorders,including the enhancement of spontaneous locomotor activity and cognitive impairment.
基金supported by Marmara University Scientific Research Council, Turkey (BGS-150107-0011)
文摘The inhibitory sources in the thalamic nuclei are local interneurons and neurons of the thalamic reticular nucleus. Studies of models of absence epilepsy have shown that the seizures are associated with an excess of inhibitory neurotransmission in the thalamus. In the present study, we used light- microscopic gamma-aminobutyric acid （GABA） immunocytochemistry to quantify the interneurons in the lateral geniculate （LGN）, ventral posteromedial （VPM）, and ventral posterolateral （VPL） thalamic nuclei, and compared the values from normal Wistar rats and genetic absence epilepsy rats from Strasbourg （GAERS）. We found that in both Wistar rats and GAERS, the proportion of interneurons was significantly higher in the LGN than in the VPM and VPL. In the LGN of Wistar rats, 16.4% of the neurons were interneurons and in the GAERS, the value was 15.1%. In the VPM, the proportion of interneurons was 4.2% in Wistar and 14.9% in GAERS; in the VPL the values were 3.7% for Wistar and 11.1% for the GAERS. There was no significant difference between Wistar rats and the GAERS regarding the counts of interneurons in the LGN, whereas the VPM and VPL showed significantly higher counts in GAERS. Comparison of the mean areas of both relay cells and interneuronal profiles showed no significant differences between Wistar rats and GAERS. These findings show that in the VPL and the VPM there are relatively more GABAergic interneurons in GAERS than in Wistar rats. This may represent a compensatory response of the thalamocortical circuitry to the absence seizures or may be related to the production of absence seizures.
基金supported by the National Natural Science Foundation of China(32130044,31630029,32171094,and 32100930)the National Key Research and Development Program of China(2021ZD0202500).
文摘Autapses selectively form in specific cell types in many brain regions.Previous studies have also found putative autapses in principal spiny projection neurons(SPNs)in the striatum.However,it remains unclear whether these neurons indeed form physiologically functional autapses.We applied whole-cell recording in striatal slices and identified autaptic cells by the occurrence of prolonged asynchronous release(AR)of neurotransmitters after bursts of high-frequency action potentials(APs).Surprisingly,we found no autaptic AR in SPNs,even in the presence of Sr^(2+).However,robust autaptic AR was recorded in parvalbumin(PV)-expressing neurons.The autaptic responses were mediated by GABA_(A) receptors and their strength was dependent on AP frequency and number.Further computer simulations suggest that autapses regulate spiking activity in PV cells by providing self-inhibition and thus shape network oscillations.Together,our results indicate that PV neurons,but not SPNs,form functional autapses,which may play important roles in striatal functions.
基金supported by the National Natural Science Foundation of China(32430044,32127801,and 32300833)the National Key R&D Program of China(2021YFA0805000)the Fund by China Postdoctoral Science Foundation(2022M720571)。
文摘Tonotopy,the spatial organization of neurons based on their sound frequency responses,is a fundamental feature of the auditory pathway,extending from the cochlea to the auditory cortex.While excitatory neurons have been considered necessary for tonotopy in the cortex,the role of inhibitory interneurons remains unclear.Using a novel two-channel widefield Ca~(2+)imaging system,the 2-Channel Alternating exposure wide-Field Explorer(2-CAFE),we simultaneously measured the sound responsiveness of distinct neuron types in awake mice.Combined with two-photon imaging,we observed that GABAergic interneurons followed a similar tonotopic organization to the conventional auditory maps at both mesoscale and single-cell resolutions.Among the major interneuron subtypes—parvalbumin(PV),somatostatin(SST),and vasoactive intestinal peptide(VIP)—PV interneurons demonstrated a critical role in maintaining tonotopy.Inactivation of PV neurons,but not VIP or SST neurons,significantly weakened the tonotopic strength in the auditory cortex.These findings establish PV interneurons as essential components of auditory cortical tonotopy.
基金supported by the National Natural Science Foundation of China(81971058,82371226,82101295,82301398)the National Funded Postdoctoral Researcher Program(GZC20233585)The Boost Plan of Xijing Hospital(XJZT24QN25,XJZT25CX22).
文摘Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.
基金funding provided by Karolinska Institute.This work was supported by the Swedish Research Council,the Swedish Brain Foundation,the Swedish Alzheimer Foundation,theÅhlén Foundation(AF),the Berger Foundation(TD),the Olle Engkvist Foundation(TD),G&K Kock Foundation(TD),the Strategic Research Area MultiPark at Lund University(TD),the Foundation for Geriatric Diseases at Karolinska Institutet,theÅhlén Foundation(YAT),Consejo Nacional de Ciencia y Tecnología(CONACYT)postdoctoral fellowships and StratNeuro program at Karolinska Institutet(LEAG),Lindhés Advokabyra AB Grant and Stohnes Stiftelse(LEAG,YAT)the Spanish Ministerio de Ciencia e Innovación(MICIN/AEI/FEDER:PID2019-107677 GB-I00,ARM).
文摘Background Alzheimer’s disease(AD)is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists.Neuroinflammation is central to the pathology progression,with evidence suggesting that microglia-released galectin-3(gal3)plays a pivotal role by amplifying neuroinflammation in AD.However,the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown.Methods Here,we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo(20-80 Hz)by performing electrophysiological recordings in the hippocampal CA3 area of wild-type(WT)mice and of the 5×FAD mouse model of AD.In addition,the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes,and amyloid-β(Aβ)plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout(KO).Results Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner,which was accompanied by impairment of cellular dynamics in fast-spiking interneurons(FSNs)and pyramidal cells.We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139,which also prevented Aβ42-induced degradation of gamma oscillations.Further-more,the 5×FAD mice lacking gal3(5×FAD-Gal3KO)exhibited WT-like gamma network dynamics and decreased Aβplaque load.Conclusions We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs,inducing a network performance collapse.Moreover,our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.
