Neuroligin-2 controls the establishment of fast GABAergic transmission in adult-born granule cells.
Neuroligin-2 controls the establishment of fast GABAergic transmission in adult-born granule cells.
复制标题
Neuroligin-2 控制成年颗粒细胞中快速 GABA 能传输的建立。
DOI：
10.1002/hipo.23505
复制
发表时间：
2023
期刊：
影响因子：
3.5
通讯作者：
Schinder,AlejandroF
中科院分区：
文献类型：
--
作者：
Groisman,AyelénI;Aguilar-Arredondo,Andrea;Giacomini,Damiana;Schinder,AlejandroF
GABA能抑制对于神经元尖峰的精确性和脑中网络活动的稳态调节至关重要。成年神经发生挑战网络的稳态，因为新的颗粒细胞（GC）不断整合在功能性齿状回。在发育过程中，由于小清蛋白中间神经元（PV-IN）对体周GABA能抑制的成熟延迟，成年出生的GC经历了短暂的兴奋性增强状态。这种延迟的突触成熟的机制仍然未知。我们在年轻成年小鼠中检查了PV‐ IN在新GC上形成的突触的形态和功能，并研究了突触粘附分子神经连接素2（NL 2）的影响。PV‐IN终末在新GC上的体周沉积在2周时很明显，并且尺寸继续增长，在第4周达到稳定水平。通过在新GC中表达短发夹RNA（shNL 2）来突触后敲低NL 2导致突触接触的尺寸更小，囊泡GABA转运蛋白VGAT的体周沉积面积减少，以及突触前活性位点的数量减少。与对照GC相比，表达shNL 2的GC表现出自发的GABA能反应，频率和幅度降低，动力学也较慢。此外，PV-IN的光遗传学刺激诱发的突触后反应表现出缓慢的动力学、增加的配对脉冲比和具有NL 2敲低的GC中的变异系数，这表明活跃突触的数量以及神经递质释放（Pr）的概率减少。我们的研究结果表明，由PV‐ IN在成年出生的GC上形成的突触继续发育超过解剖生长点，并且需要NL 2进行结构和功能成熟，伴随着向快速GABA能传递的转换。
GABAergic inhibition is critical for the precision of neuronal spiking and the homeostatic regulation of network activity in the brain. Adult neurogenesis challenges network homeostasis because new granule cells (GCs) integrate continuously in the functional dentate gyrus. While developing, adult‐born GCs undergo a transient state of enhanced excitability due to the delayed maturation of perisomatic GABAergic inhibition by parvalbumin interneurons (PV‐INs). The mechanisms underlying this delayed synaptic maturation remain unknown. We examined the morphology and function of synapses formed by PV‐INs onto new GCs over a 2‐month interval in young adult mice, and investigated the influence of the synaptic adhesion molecule neuroligin‐2 (NL2). Perisomatic appositions of PV‐IN terminals onto new GCs were conspicuous at 2 weeks and continued to grow in size to reach a plateau over the fourth week. Postsynaptic knockdown of NL2 by expression of a short‐hairpin RNA (shNL2) in new GCs resulted in smaller size of synaptic contacts, reduced area of perisomatic appositions of the vesicular GABA transporter VGAT, and the number of presynaptic active sites. GCs expressing shNL2 displayed spontaneous GABAergic responses with decreased frequency and amplitude, as well as slower kinetics compared to control GCs. In addition, postsynaptic responses evoked by optogenetic stimulation of PV‐INs exhibited slow kinetics, increased paired‐pulse ratio and coefficient of variation in GCs with NL2 knockdown, suggesting a reduction in the number of active synapses as well as in the probability of neurotransmitter release (Pr). Our results demonstrate that synapses formed by PV‐INs on adult‐born GCs continue to develop beyond the point of anatomical growth, and require NL2 for the structural and functional maturation that accompanies the conversion into fast GABAergic transmission.