Neurexin-1β/neuroligin-2介导神经微环路兴奋-抑制失衡在神经病理性疼痛与抑郁共病中的作用

Our previous studies have shown that the damage of nerve could cause the comorbidity of neuropathic pain and depression in adult mice, accompanied with the weakness of gamma oscillation, the decrease of inhibitory postsynaptic potential, and long-term potentiation (LTP) impairment, However, the underlying mechanisms are unknown. For these reasons: 1) the neuronal microcirculatory is composed of PV interneuron and pyramidal neuron, its imbalance is relation with many neurological and psychotic disorders; 2) PV intermediate neurons produce inhibitory postsynaptic potentials on pyramidal neurons and regulate pyramidal neurons to produce gamma oscillations 3) neurexin-1/neuroligin-2 regulates the development of inhibitory synapse between PV interneuron and pyramidal neuron specifically; we hypothesize that the damage of nerve could cause down-regulation of Nrx-1β/Nlg-2, neuronal microcirculation dysfunction of PV interneurons and pyramidal neurons, the weakness of gamma oscillation, the impairment of synaptic plasticity, the occurrence of neuropathic pain and depression. This project intends to reveal the new mechanism of neuropathic pain-depression comorbidity from the molecular-cell-network-overall level by using behavioral, electrophysiological, transgenic, molecular biology and other techniques.

我们前期研究表明：慢性坐骨神经损伤致成年小鼠神经病理性疼痛与抑郁共病，伴随海马γ振荡减弱、抑制性突触后电位降低、长时程增强受损。然而，机制仍不清，鉴于：1）微清蛋白（PV）中间神经元与锥体神经元形成神经微环路，而神经微环路兴奋-抑制失衡与疼痛和抑郁发生密切相关；2）PV中间神经元对锥体神经元产生抑制性突触后电位并调控锥体神经元产生γ振荡；3）neurexin-1β（Nrx-1β）/neuroligin-2（Nlg-2）介导PV中间神经元与锥体神经元抑制性突触的形成；我们推测：神经损伤引起Nrx-1β/Nlg-2信号下调，导致抑制性突触受损，PV中间对锥体神经元抑制作用降低及γ振荡减弱，引起神经微环路兴奋-抑制失衡及突触可塑性受损，出现神经病理性疼痛与抑郁共病。本课题通过运用行为学、神经电生理、转基因、分子生物学等技术，从分子—突触—细胞—微环路水平揭示神经病理性疼痛与抑郁共病发生的新机制。

神经病理性疼痛（neuropathic pain）是指由外周或中枢水平躯体感觉神经系统的损伤或疾病直接造成的疼痛。抑郁症（depression）是一种常见的心理疾病，表现为至少持续两周的情绪低落和/或快感缺乏，甚至伴有自杀观。流行病学研究显示42%的神经病理性疼痛患者出现抑郁症状，同样抑郁患者有37%出现疼痛症状。神经病理性疼痛与抑郁共病患者的治疗比单纯神经病理性疼痛或抑郁症的治疗更复杂。因此，研究神经病理性疼痛与抑郁共病的发病机制，寻找新的治疗靶点尤为重要。. 通过前期研究，我们得到一些初步结果：.（1）神经损伤小鼠出现了明显的痛阈降低、抑郁样行为和空间工作记忆损伤；（2）给与右旋氯胺酮可以明显缓解抑郁样行为和空间工作记忆损伤，同时海马中BDNF明显增加；（3）在强迫游泳诱导的急性抑郁模型中，海马中γ-氨基丁酸明显降低，给与γ-氨基丁酸（GABA）受体A抑制剂荷包牡丹碱（Bic）明显降低急性抑郁小鼠不动时间，增加海马GABA含量；（4）在强迫游泳诱导的急性抑郁模型中，γ-氨基丁酸（GABA）受体A拮抗剂Bic可以明显增加GAD65表达及星形胶质细胞的可塑性。