Reversible activation of critical period plasticity in visual cortex

项目概要/摘要 弱视是由单眼剥夺（MD）引起的，它改变了刺激的选择性 初级视觉皮层的神经元。利用该模型的先前研究确定， MD诱导的神经选择性是兴奋性突触重组的结果 兴奋性皮质神经元，这是由抑制性GABA能网络组成的调节， 小清蛋白阳性抑制性中间神经元（PVINs）。一个正在形成的共识是， 皮层2/3层中PVIN回路的抑制是下游兴奋性突触的可塑性所需的， 并且高于或低于允许范围的抑制了对MD的反应。因此，委员会认为， 抑制的发展加强触发了关键期的开始;在后期阶段， 通过减少PV IN的募集来实现“允许的”抑制范围。 在这里，我们确定了2/3层PV IN上的激励的可塑性作为电路调节的关键位点。 重组V1。我们的初步数据表明，对MD的初始反应是快速和短暂的， 消除局部锥体神经元（Pyr）与PV INS之间的兴奋性连接。 MD，我们发现约50%的本地L2/3 Pyrà Pyrà PV-IN连接被消除。重要的是， L2/3 Pyr和来自第4层Pyr的激发保持不变。这种全有或全无的消除特定的 连接与突触结构的丢失一致，是短暂的，并在3 MD的日子我们的初步结果还表明，MD诱导的近端L2/3的消除， Pyrà pv INs输入依赖于mGluR 5激活，并受到活性非依赖性 神经元五聚蛋白2（NPTX 2）。我们认为，快速mGluR 5和NPTX 2依赖性消除局部 L2/3 Pyrà Pyrà PV INs连接是随后眼优势改变的必要初始步骤， MD诱导的空间视敏度。因此，我们发现NPTX 2的积累阻止了L2/3 Pyrà Pyrà PV IN 消除和眼优势可塑性。相反，成人显性阴性NPTX 2的表达 重新激活L2/3 Pyrà Pyrà PV IN的消除和眼优势可塑性对MD的反应 我们提出了一系列多学科的实验来测试这个模型的有效性，该模型结合了联合收割机， Quinlan实验室在评估体内生理学和柯克伍德的生理变化方面的专业知识 实验室在确定的神经元之间的单个突触的变化的评估。我们将检验这个假设 L2/3 Pyrà PV INs兴奋性突触的消除是1）局部的，短暂的，仅限于出生后 关键期2）依赖于mGluR和NPTX 2信号传导和3）随后的强制性初始步骤 MD引起的眼优势和空间敏锐度的变化。我们的模型预测， 周期直接反映了L2/3 Pyrà Pyrà PV-IN可塑性的丧失，这与许多广泛持有的 关于哺乳动物皮层突触可塑性发育变化的假设。

Project Summary/Abstract Amblyopia is induced in model systems by monocular deprivation (MD), which changes the stimulus selectivity of neurons in the primary visual cortex. Prior research utilizing this model established that the changes in neural selectivity induced by MD result from the reorganization of excitatory glutamatergic cortical synapses onto excitatory cortical neurons, which is regulated by an inhibitory GABAergic network composed of parvalbumin positive inhibitory interneurons (PV INs). An emerging consensus is that a permissive level of inhibition from PV IN circuits in cortical layer 2/3 is required for plasticity at downstream excitatory synapses, and that inhibition above or below the permissive range constrains the response to MD. Accordingly, developmental strengthening of inhibition triggers the onset of the critical period; at later stages, the “permissive” range of inhibition is achieved by reductions the recruitment of PV INs. Here we identify the plasticity of excitation onto layer 2/3 PV INs as a critical locus for the regulation of circuit reorganization in V1. Our preliminary data demonstrate that the initial response to MD is a rapid and transient elimination of excitatory connections made by local pyramidal neurons (Pyr) onto PV INs. Following 1 day of MD, we find that ~50% of local L2/3 PyràPV-IN connections are eliminated. Importantly, synapses from distal L2/3 Pyrs and excitation from layer 4 Pyrs remains unchanged. This all-or-none elimination of specific connections coincides with the loss of synaptic structure, is transient, and returns to control values following 3 days of MD. Our preliminary results also demonstrate that the MD-induced elimination of proximal L2/3 PyràPV INs inputs depends on mGluR5 activation and is inhibited by expression of activity-independent neuronal pentraxin 2 (NPTX2). We propose that the rapid mGluR5 and NPTX2-dependent elimination of local L2/3 PyràPV INs connection is an obligatory initial step for subsequent changes in ocular dominance and spatial acuity induced by MD. Accordingly, we show that accumulation of NPTX2 prevents L2/3 PyràPV IN elimination and ocular dominance plasticity. Conversely, expression of dominant negative NPTX2 in adults reactivates the elimination of L2/3 PyràPV INs and ocular dominance plasticity in response to MD We propose a series of multidisciplinary experiments to test the validity of this model that combine the expertise of the Quinlan lab in the assessment of physiological changes in vivo physiology and the Kirkwood lab in the assessment of changes in single synapses between identified neurons. We will test the hypothesis that the elimination of L2/3 PyràPV INs excitatory synapses is 1) local, transient and confined to a postnatal critical period 2) dependent on mGluR and NPTX2 signaling and 3) an obligatory initial step for subsequent changes in ocular dominance and spatial acuity induced by MD. Our model predicts that the end of the critical period reflects directly the loss of L2/3 PyràPV-IN plasticity, which departs from many widely-held assumptions regarding developmental changes in synaptic plasticity in the mammalian cortex.