Sato Kohji
Department of Organ & Tissue Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu, Shizuoka 431-3192, Japan.
Med Hypotheses. 2020 Oct;143:109901. doi: 10.1016/j.mehy.2020.109901. Epub 2020 May 30.
Prepulse inhibition (PPI) of acoustic startle reflex is a measure of sensorimotor gating that may reflect the biological processes underlying gaiting impairments in schizophrenia. Although PPI is clinically useful, why PPI is inhibited in schizophrenia is largely unknown. Prepulse inhibition is mediated by M2-like muscarinic acetylcholine receptor on neurons in the caudal pontine reticular nucleus (PnC), activation of this receptor induces Gαi dissociation, and inhibits adenylyl cyclase, resulting in the inhibition of the neurons. On the other hand, the symptoms of schizophrenia are mainly linked to hyperactive dopaminergic activity, mediated by dopamine D2-like receptor. Interestingly, D2-like receptor also uses Gαi. This means that both M2-like acetylcholine receptor and D2-like dopamine receptor use same Gαi-protein, competitively. Thus, chronic over-activation of D2-like receptor observed in schizophrenia may disrupt normal M2-like acetylcholine receptor functions due to their shared coupling to Gαi-proteins, i.e. by reducing the amount of Gαi-protein available for M2-like acetylcholine receptors, resulting in the impairment of PPI.
听觉惊吓反射的前脉冲抑制（PPI）是一种感觉运动门控的测量方法，可能反映精神分裂症步态障碍背后的生物学过程。虽然PPI在临床上有用，但精神分裂症中PPI被抑制的原因在很大程度上尚不清楚。前脉冲抑制由尾侧脑桥网状核（PnC）神经元上的M2样毒蕈碱型乙酰胆碱受体介导，该受体的激活诱导Gαi解离，并抑制腺苷酸环化酶，从而导致神经元受到抑制。另一方面，精神分裂症的症状主要与多巴胺能活性亢进有关，由多巴胺D2样受体介导。有趣的是，D2样受体也使用Gαi。这意味着M2样乙酰胆碱受体和D2样多巴胺受体竞争性地使用相同的Gαi蛋白。因此，在精神分裂症中观察到的D2样受体慢性过度激活可能会破坏正常的M2样乙酰胆碱受体功能，因为它们与Gαi蛋白共同偶联，即通过减少可用于M2样乙酰胆碱受体的Gαi蛋白量，导致PPI受损。
