Postnatal development of nicotinic acetylcholine receptor signaling in the cerebral cortex

可靠的突触传递对于感觉皮层回路的有序发展至关重要。为了实现这一点，受体需要聚集在神经元的关键位置，以控制净兴奋性。受体运输和聚集的中断可能会导致大脑功能的严重损害。到目前为止，对受体聚集的研究大多集中在神经肌肉接头的胆碱能突触或发育中的中枢神经系统中的谷氨酸和GABA受体。然而，随着深层组织双光子成像和荧光标记尼古丁受体基因工程的发展，现在可以追踪nAChR在完整的出生后大脑中的运输和聚集。来自我的实验室的初步荧光和电子显微镜数据清楚地表明，在建立正常感觉皮质功能的出生后发育的关键时期，nAChR在躯体感觉皮质中的分布发生了戏剧性的变化。拟议的实验试图了解nAChR运输的发育时间表和细胞特异性，什么结合蛋白调节这一过程，最终，在大脑皮层中适当的nAChR发育和信号传递的功能意义是什么？

Reliable synaptic transmission is critical for the orderly development of sensory cortical circuits. In order for this to occur, receptors need to cluster at strategic sites in neurons to control net excitability. Disruptions in receptor trafficking and clustering can lead to profound impairments in brain function. Thus far, most studies of receptor clustering have focused on cholinergic synapses at the neuromuscular junction or glutamate and GABA receptors in the developing central nervous system. However, with the development of deep tissue 2-photon imaging and genetic engineering of fluorescently tagged nicotinic receptors, it is now possible to track nAChR trafficking and clustering in the intact postnatal brain. Preliminary fluorescence and electron microscopy data from my lab clearly indicate that there are dramatic changes in distribution of nAChR in the somatosensory cortex during a critical period of post-natal development where normal sensory cortical function is established. The proposed experiments seek to understanding the developmental time table and cell specificity of nAChR trafficking, what binding proteins regulate this process and ultimately, what is the functional significance of proper nAChR development and signalling in the cerebral cortex?