Schizophrenia risk-gene Crmp2 deficiency causes precocious critical period plasticity and deteriorated binocular vision

精神分裂症易感基因Crmp2缺失导致发育关键期可塑性提前与双眼视觉功能缺陷

Brain-specific loss of a microtubule-binding protein collapsin response mediator protein-2(CRMP2)in the mouse recapitulates many schizophrenia-like behaviors of human patients,possibly resulting from associated developmental deficits in neuronal differentiation,path-finding,and synapse formation.However,it is still unclear how the Crmp2 loss affects neuronal circuit function and plasticity.By conducting in vivo and ex vivo electrophysiological recording in the mouse primary visual cortex(V1),we reveal that CRMP2 exerts a key regulation on the timing of postnatal critical period(CP)for experience-dependent circuit plasticity of sensory cortex.In the developing V1,the Crmp2 deficiency induces not only a delayed maturation of visual tuning functions but also a precocious CP for visual input-induced ocular dominance plasticity and its induction activity–coincident binocular inputs right after eye-opening.Mechanistically,the Crmp2 deficiency accelerates the maturation process of cortical inhibitory transmission and subsequently promotes an early emergence of balanced excitatory-inhibitory cortical circuits during the postnatal development.Moreover,the precocious CP plasticity results in deteriorated binocular depth perception in adulthood.Thus,these findings suggest that the Crmp2 deficiency dysregulates the timing of CP for experience-dependent refinement of circuit connections and further leads to impaired sensory perception in later life.

CRMP2(collapsin response mediator protein2)参与细胞骨架和囊泡运输的动态调控.Crmp2全脑敲除的小鼠表现出多种精神分裂症样异常行为,这可能与Crmp2缺失所致的神经发育异常相关.但Crmp2缺失是否直接影响神经环路的功能发育与可塑性仍不清楚.本研究发现CRMP2对调控出生后初级视皮层(V1)的发育关键期可塑性的开启至关重要.Crmp2缺失可导致V1神经元的视觉选择性功能发育迟缓,并显著地提前V1发育关键期—视觉经验依赖的眼优势可塑性及其诱导的神经活动(双眼输入同步化)机制都提前发生.Crmp2缺失特异地加速了皮层环路中抑制性突触功能的发育成熟,进而提前了兴奋-抑制平衡的建立时间.视崖行为测试表明,这些关键期提前开启的Crmp2敲除小鼠在成年后表现出双眼深度感知功能的缺陷.因此,精神分裂症易感基因Crmp2的缺失可引发异常的脑发育关键期可塑性,进而造成大脑感知觉功能的长期缺陷.