Neural stem cell (NSC) hypofunction is an etiological hypothesis of schizophrenia. Although dopamine (DA) dysfunction is also a widely accepted hypothesis, molecular background of mesolimbic DA hyperactivity has not y...Neural stem cell (NSC) hypofunction is an etiological hypothesis of schizophrenia. Although dopamine (DA) dysfunction is also a widely accepted hypothesis, molecular background of mesolimbic DA hyperactivity has not yet been well known. Here, the author proposes “D-cell hypothesis”, accounting for molecular basis of mesolimbic DA hyperactivity of schizophrenia, by NSC hypofunction and decrease of putative NSC-induced D-cells. The “D-cell” is defined as “non-monoaminergic aromatic L-amino acid decarboxylase (AADC)-containing cell”. D-cells produce trace amines, and also take up amine precursors and convert them to amines by decarboxylation. The author reported “dopa-decarboxylating neurons specific to the human striatum”, that is, “D-neurons” in the human striatum, and decrease of striatal D-neurons in patients with schizophrenia. Trace amine-associated receptor, type 1 (TAAR1), a subtype of trace amine receptors, having a quite number of ligands such as tyramine, β-phenylethylamine (PEA) and methamphetamine, has modulating functions on monoamine neurons. It has been known that reduced binding of ligands to TAAR1 receptors on DA terminal of DA neurons of the midbrain ventral tegmental area (VTA) increased firing frequency of VTA DA neurons. In brains of schizophrenia, NSC hypofunction in the subventricular zone of lateral ventricle may cause decrease of D-neurons in the striatum and nucleus accumbens, and may result in decrease of trace amine signals. Decrease of trace amine signals to TAAR1 on VTA DA neurons may increase firing frequency of VTA DA neurons, and may finally cause mesolimbic DA hyperactivity. Increased stimulation to DA D2 receptors of NSCs might suppress NSC proliferation, and may induce additional mesolimbic DA hyperactivity as well as D-cell decrease. This novel theory, “D-cell hypothesis”, possibly explains mesolimbic DA hyperactivity in pathogenesis of schizophrenia.展开更多
Recent pharmacological discovery on trace amine-associated receptor, type 1(TAAR1) has emphasized importance of trace amines in pathogenesis of psychoses, such as schizophrenia. TAAR1 has many ligands, including tyram...Recent pharmacological discovery on trace amine-associated receptor, type 1(TAAR1) has emphasized importance of trace amines in pathogenesis of psychoses, such as schizophrenia. TAAR1 has many ligands, including tyramine, β-phenylethylamine (PEA), amphetamines, and 3’-iodothyronamine. So-called D-neurons are putative producer of trace amines, endogenous ligands of TAAR1. The D-neuron is defined “the aromatic L-amino acid decarboxylase (AADC)-containing neuron, but not dopaminergic nor serotonergic”, i.e. not containing tyrosine hydroxylase nor tryptophan hydroxylase. AADC is an enzyme, also called dopa decarboxylase (DDC). The localization of D-neurons in the central nervous system has been specified into 15 groups, from the spinal cord (D1) to striatum (D15). We showed the decrease of D-neurons in D15 in postmortem brains of schizophrenia, where midbrain dopamine (DA) neurons are heavily innervated. Decrease of D-neurons may cause reduction of trace amines in the striatum, and may also decrease stimulation of TAAR1 on striatal terminals of ventral tegmental area (VTA) DA neurons. This might increase firing frequency of VTA DA neurons, and causes DA hyperactivity in the striatum and nucleus accumbens. In the present article, the author introduces the novel theory, “D-cell hypothesis”, for mesolimbic DA hyperactivity of schizophrenia. Some clinical and/or experimental evidences that support this hypothesis are mentioned. The D-neuron, as a trace amine producer, is a clue for elucidating pathogenesis of psychoses, as well as human mental functions. Thus, signal transduction of D-neurons should be investigated.展开更多
文摘Neural stem cell (NSC) hypofunction is an etiological hypothesis of schizophrenia. Although dopamine (DA) dysfunction is also a widely accepted hypothesis, molecular background of mesolimbic DA hyperactivity has not yet been well known. Here, the author proposes “D-cell hypothesis”, accounting for molecular basis of mesolimbic DA hyperactivity of schizophrenia, by NSC hypofunction and decrease of putative NSC-induced D-cells. The “D-cell” is defined as “non-monoaminergic aromatic L-amino acid decarboxylase (AADC)-containing cell”. D-cells produce trace amines, and also take up amine precursors and convert them to amines by decarboxylation. The author reported “dopa-decarboxylating neurons specific to the human striatum”, that is, “D-neurons” in the human striatum, and decrease of striatal D-neurons in patients with schizophrenia. Trace amine-associated receptor, type 1 (TAAR1), a subtype of trace amine receptors, having a quite number of ligands such as tyramine, β-phenylethylamine (PEA) and methamphetamine, has modulating functions on monoamine neurons. It has been known that reduced binding of ligands to TAAR1 receptors on DA terminal of DA neurons of the midbrain ventral tegmental area (VTA) increased firing frequency of VTA DA neurons. In brains of schizophrenia, NSC hypofunction in the subventricular zone of lateral ventricle may cause decrease of D-neurons in the striatum and nucleus accumbens, and may result in decrease of trace amine signals. Decrease of trace amine signals to TAAR1 on VTA DA neurons may increase firing frequency of VTA DA neurons, and may finally cause mesolimbic DA hyperactivity. Increased stimulation to DA D2 receptors of NSCs might suppress NSC proliferation, and may induce additional mesolimbic DA hyperactivity as well as D-cell decrease. This novel theory, “D-cell hypothesis”, possibly explains mesolimbic DA hyperactivity in pathogenesis of schizophrenia.
文摘Recent pharmacological discovery on trace amine-associated receptor, type 1(TAAR1) has emphasized importance of trace amines in pathogenesis of psychoses, such as schizophrenia. TAAR1 has many ligands, including tyramine, β-phenylethylamine (PEA), amphetamines, and 3’-iodothyronamine. So-called D-neurons are putative producer of trace amines, endogenous ligands of TAAR1. The D-neuron is defined “the aromatic L-amino acid decarboxylase (AADC)-containing neuron, but not dopaminergic nor serotonergic”, i.e. not containing tyrosine hydroxylase nor tryptophan hydroxylase. AADC is an enzyme, also called dopa decarboxylase (DDC). The localization of D-neurons in the central nervous system has been specified into 15 groups, from the spinal cord (D1) to striatum (D15). We showed the decrease of D-neurons in D15 in postmortem brains of schizophrenia, where midbrain dopamine (DA) neurons are heavily innervated. Decrease of D-neurons may cause reduction of trace amines in the striatum, and may also decrease stimulation of TAAR1 on striatal terminals of ventral tegmental area (VTA) DA neurons. This might increase firing frequency of VTA DA neurons, and causes DA hyperactivity in the striatum and nucleus accumbens. In the present article, the author introduces the novel theory, “D-cell hypothesis”, for mesolimbic DA hyperactivity of schizophrenia. Some clinical and/or experimental evidences that support this hypothesis are mentioned. The D-neuron, as a trace amine producer, is a clue for elucidating pathogenesis of psychoses, as well as human mental functions. Thus, signal transduction of D-neurons should be investigated.
文摘目的观察吡咯喹啉醌(PQQ)对D-半乳糖(D-gal)致大鼠海马神经细胞衰老的影响。方法用大剂量D-gal致大鼠脑老化模型,侧脑室注射PQQ,50 d后行脑组织切片H-E染色和尼氏染色,观察海马神经元的形态学变化,流式细胞仪检测细胞的凋亡率;用TBA法和Fenton反应测海马组织自由基含量;W estern b lot观察C-FOS蛋白的表达。结果D-gal处理组鼠海马神经元胞体变小,尼氏小体的吸光度值(A)降低,细胞凋亡率和自由基含量增加,C-FOS蛋白的表达降低;而同时PQQ处理后,与对照组相比海马神经元的胞体变大,尼氏小体的A值增加,自由基含量和神经元的凋亡率无明显增加,PQQ剌激了C-FOS蛋白的表达。结论PQQ能延缓D-gal引起的大鼠海马神经细胞衰老。
