Inhibitory plasticity in visual cortical circuits

描述(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，所有信息汇聚和处理的地方，塑造着我们的感知，也被我们的感知塑造着。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等人，2006年；MR-Flogel等人，2006年)。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其重要，此时神经回路的高度精炼时期--关键时期--会导致大脑功能成熟和健康(Hubel和Wisel，1970；Katz和Shatz，1996；Morales等人，2002；Hensch，2005)。在初级视皮层中，突触特定形式的可塑性，如长时程增强(LTP)或抑制(LTD)，是视神经元功能的基本机制(Smith等，2009)，是经验依赖性可塑性研究最好的模型之一。抑制性突触参与调节关键期的开始和持续时间，证明了抑制性突触在皮层环路中的中心作用(Hensch等人，1998；Fagiolini和Hensch，2000；Fagiolini等人，2004)。由快速放电中间神经元(FS)介导的抑制性突触传递直接受到经验的影响(Maffei等人，2004；Maffei等人，2006)。一种新的可塑性形式-FS对锥体神经元突触的LTP，LTPI-是在第四层由视觉驱动的变化诱导的。LTPI可能有助于形成视觉皮质神经元的反应和感受野；但如果在最大或饱和水平诱导，如视觉剥夺后测量的水平，它可能会促进功能丧失(Maffei等人，2006年)。LTPI诱导性质是本提案的主题。最新的电生理学技术将被用来剖析LTPI的诱导机制。更具体地说，我们将确定1)LTPI诱导对FS和锥体神经元活动的时间的依赖；2)LTPI对符合检测机制的要求；3)它对突触后神经元活动范围的依赖-阈值下与阈值上；4)LTPI对突触前放电频率的依赖。我们还将开始研究LTPI的细胞机制：对钙内流的依赖和参与GABAA受体在突触的运输的细胞内通路-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Msing，2005)。将从锥体和FS获得四个并发的膜片钳记录，以测量单突触抑制连接的强度、动力学和可塑性。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通路。 与公共健康相关：视觉体验在发育过程中塑造大脑皮层回路。突触将环境输入转化为神经元整合的信号，神经元进而对感觉刺激产生适当的反应(Huberman等人，2006年；Mr Sic-Flogel等人，2006年)。最近关于抑制性突触和可塑性关键期的开始和持续时间的调节的发现证明了抑制性突触传递在视觉皮质回路中所起的中心作用(Hensch等人，1998；Hensch，2005)。视皮层抑制性突触的成熟和可塑性对于视觉输入的处理和平衡回路兴奋性的保持是必不可少的(Rozas等人，2001；Morales等人，2002；Hensch和Fagiolini，2005)。

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).