Inhibitory plasticity in visual cortical circuits

描述（由申请人提供）：作为孩子，我们需要学习无限的技能。我们的大脑是所有信息汇聚和处理的地方，它塑造并被我们的感知所塑造。突触将环境输入传递给神经元，这些信号的整合决定了神经元对特定刺激的反应（Huberman et al., 2006; mrsicflogel et al., 2006）。当突触被相关输入激活时，神经可塑性调节突触的强度。可塑性在大脑发育过程中尤为重要，因为神经回路的高度完善时期——关键时期——会导致大脑成熟和健康的功能（Hubel和Wiesel, 1970； Katz和Shatz, 1996； Morales等人，2002;Hensch, 2005）。在初级视觉皮层中，研究得最好的经验依赖可塑性模型之一，突触特定形式的可塑性，如长期增强（LTP）或抑制（LTD）是视觉神经元功能的基本机制（Smith等人，2009）。抑制性突触传递在皮层回路中的核心作用是通过抑制性突触参与调节关键时期的开始和持续时间来证明的（Hensch等人，1998；Fagiolini和Hensch, 2000； Fagiolini等人，2004）。由快速峰值中间神经元介导的抑制性突触传递（FS）直接受到经验的影响（Maffei et al., 2004; Maffei et al., 2006）。一种新的可塑性形式- FS到锥体神经元突触的LTP， LTPi -是由视觉驱动的变化在第4层诱导的。LTPi可能有助于形成视觉皮质神经元的反应性和感受野；但如果达到最大或饱和水平，例如在视觉剥夺后测量的水平，则可能会促进功能丧失（Maffei等，2006）。LTPi的感应特性是本提案的主题。最先进的电生理技术将用于剖析诱导LTPi的机制。更具体地说，我们将确定1)LTPi诱导对FS和锥体神经元活动时间的依赖；2)符合检测机制的LTPi要求；3)对突触后神经元活动范围的依赖性——阈下与阈上；4) LTPi对突触前放电频率的依赖性。我们还将开始研究LTPi的细胞机制：依赖钙内流和突触中GABAA受体运输的细胞内通路- PKA (Poisbeau等人，1999)-以及GABAA受体功能的调节- PKC （Poisbeau等人，1999；Brandon等人，2000；Song和Messing， 2005）。将从锥体和FS获得四重并发膜片钳记录，以测量单突触抑制性连接的强度、动态和可塑性。将应用特定的药物来防止LTPi的诱导，并开始识别参与其诱导的细胞途径。

DESCRIPTION (provided by applicant): As children we need to learn an infinite set of skills. Our brain, the site where all information converges and is processed, shapes and is shaped by our perception. Synapses transfer environmental inputs to neurons and the integration of these signals determines the neuronal response to a specific stimulus (Huberman et al., 2006; Mrsic-Flogel et al., 2006). Neural plasticity modulates the strength of synapses when they are activated by relevant inputs. Plasticity is particularly important during brain development when periods of intense refinement of neural circuits - critical periods - lead to a mature and healthy functioning brain (Hubel and Wiesel, 1970; Katz and Shatz, 1996; Morales et al., 2002; Hensch, 2005). In primary visual cortex, one of the best studied models for experience-dependent plasticity, synapse specific forms of plasticity such as long term potentiation (LTP) or depression (LTD) are fundamental mechanisms for visual neuron function (Smith et al., 2009). The central role of inhibitory synaptic transmission in cortical circuits is demonstrated by the involvement of inhibitory synapses in the modulation of the onset and duration of critical periods (Hensch et al., 1998; Fagiolini and Hensch, 2000; Fagiolini et al., 2004). Inhibitory synaptic transmission mediated by fast spiking interneurons (FS) is directly affected by experience (Maffei et al., 2004; Maffei et al., 2006). A novel form of plasticity - LTP of FS to pyramidal neuron synapses, LTPi - is induced in layer 4 by changes in visual drive. LTPi might contribute to shaping visual cortical neurons responsiveness and receptive fields; but if induced at maximal, or saturating, levels, such as those measured after visual deprivation, it might promote loss of function (Maffei et al., 2006). LTPi induction properties are the subject of the present proposal. State of the art electrophysiological techniques will be used to dissect the mechanisms for induction of LTPi. More specifically we will determine 1) the dependence of LTPi induction on the timing of FS and pyramidal neuron activity; 2) LTPi requirement for coincidence detection mechanisms; 3) its dependence on the range of postsynaptic neuron activity - subthreshold vs. suprathreshold; 4) LTPi dependence on presynaptic frequency of firing. We will also begin to investigate the cellular mechanisms for LTPi: the dependence on calcium influx and the intracellular pathways involved in GABAA receptor trafficking at synapses- PKA (Poisbeau et al., 1999) - and in the regulation of GABAA receptor function - PKC (Poisbeau et al., 1999; Brandon et al., 2000; Song and Messing, 2005). Quadruple concurrent patch clamp recordings will be obtained from pyramidal and FS to measure the strength, dynamics and plasticity of monosynaptic inhibitory connections. Specific drugs will be applied to prevent the induction of LTPi and to begin the identification of the cellular pathways involved in its induction. PUBLIC HEALTH RELEVANCE: Visual experience shapes cortical circuits during development. Synapses translate environmental inputs into signals that are integrated by neurons, which, in turn, produce appropriate responses to the sensory stimulus (Huberman et al., 2006; Mrsic-Flogel et al., 2006). The central role played by inhibitory synaptic transmission in visual cortical circuits is demonstrated by recent findings regarding inhibitory synapses and the modulation of the onset and duration of critical periods for plasticity (Hensch et al., 1998; Hensch, 2005). The maturation and plasticity of inhibitory synapses in visual cortex are essential for the processing of visual inputs and the preservation of balanced circuit excitability (Rozas et al., 2001; Morales et al., 2002; Hensch and Fagiolini, 2005).