Activity-Dependent Synapse Refinement in the Memory Circuit in vivo

描述（由申请人提供）：功能性神经回路的形成对大脑的正常功能至关重要。有人提出，在发育的特定时期，突触连接通过神经活动得到完善，以建立适当的神经回路。海马回路由高度有序的单向突触连接组成：从内嗅皮层（EC）到齿状回（DG）到CA3到CA1再到EC。然而，尽管海马体对记忆形成、情绪处理和社会行为的重要性众所周知，但我们对海马体回路是否以及如何通过活动和这种重塑发生的发育时期来改进知之甚少。许多形式的精神疾病，如自闭症和精神分裂症，都与海马体回路的异常改变有关。因此，对海马体回路被完善的方式的理解将对这些毁灭性疾病的病因和治疗产生新的见解。在此，我们建立了一个遗传系统，在体内研究活动在小鼠海马神经回路的建立和修改中的作用。在这个系统中，我们在体内有条件地在有限的时间内灭活记忆回路中的特定神经元群，并检查灭活对神经连接的影响。我们首先研究了EC-to-DG和DG-to-CA3连接的细化。我们的初步结果表明，当在胚胎阶段失活时，失活的EC和DG轴突仍能到达合适的目标，但在发育的短时间内，由于与活跃轴突的活动依赖性竞争而被淘汰。我们的数据还表明，EC和DG轴突在不同的发育阶段被细化。利用该系统，我们将确定(1)活动何时在突触完善中发挥重要作用，(2)敏感期活动抑制是否导致永久性突触改变，(3)神经发生是否在DG中对突触完善起作用，(4)突触完善涉及哪些特定的突触变化，以及(5)微型和动作电位触发的神经传递是否在突触完善中发挥独特作用。为此，我们建议：“目标1。确定活动依赖性突触细化的敏感和关键时期。”目标2。确定在敏感期抑制活动的功能后果。”目标3。检查神经发生在DG轴突细化中的作用。”目标4。研究突触细化过程中发生了什么突触事件。”目标5。检查活动依赖性突触细化中微型和动作电位触发的神经传递的不同作用。通过这些研究，我们应该了解功能性记忆回路是如何通过神经活动在海马体中产生的。预计我们的研究将有助于我们设计预防和治疗与海马体异常回路形成相关的精神疾病的策略，如自闭症和精神分裂症。

DESCRIPTION (provided by applicant): Formation of functional neural circuits is critical for proper functioning of the brain. It has been proposed that synaptic connections are refined by neural activity during certain periods of development to establish appropriate neural circuits. Hippocampal circuits consist of highly organized unidirectional synaptic connections: from the entorhinal cortex (EC) to the dentate gyrus (DG) to CA3 to CA1 to the EC. However, despite the well known importance of the hippocampus to memory formation, emotional processing, and social behavior, we know very little about whether and how hippocampal circuits are refined by activity and the developmental periods over which such remodeling occurs. Many forms of mental illness such as autism and schizophrenia are associated with abnormal alterations in the hippocampal circuitry. Thus, the understanding of the manner by which hippocampal circuits are refined should yield novel insights into both the etiology and treatment of these devastating disorders. Here, we have established a genetic system to study the role of activity in the establishment and modification of neural circuits in the mouse hippocampus in vivo. In this system, we conditionally inactivate specific neuronal populations in the memory circuit for restricted periods of time in vivo and examine the effect of inactivation on neural connections. We first examined the refinement of EC-to-DG and DG-to-CA3 connections. Our preliminary results show that when inactivated from embryonic stages, inactive EC and DG axons still reach their appropriate target, but are eliminated during a short period of development by activity-dependent competition with active axons. Our data also suggest that EC and DG axons are refined at different developmental stages. Using this system, we will determine (1) when activity plays important roles for synapse refinement, (2) whether activity suppression during sensitive periods leads to permanent synaptic changes, (3) whether neurogenesis plays a role for synapse refinement in the DG, (4) what specific synaptic changes are involved in synapse refinement, and (5) whether miniature and action potential-triggered neurotransmission play unique roles in synapse refinement. For this, we propose to: " Aim 1. Identify the sensitive and critical periods for activity-dependent synapse refinement. " Aim 2. Determine the functional consequences of activity suppression during the sensitive periods. " Aim 3. Examine the role of neurogenesis in the refinement of DG axons. " Aim 4. Investigate what synaptic events take place during synapse refinement. " Aim 5. Examine the differential roles for miniature and action potential-triggered neurotransmission in activity- dependent synapse refinement. Through these studies we should understand how functional memory circuits are created in the hippocampus by neural activity. It is anticipated that our research will help us design strategies to prevent and treat mental illness associated with abnormal circuit formation in the hippocampus, such as autism and schizophrenia.