When a growing axon reaches its final destination in the brain, it is surrounded by multiple cell types that form a dense axonal and dendritic network. Within this complex environment, synapses form with high precision between specific pre- and post-synaptic cells. If this precision is not maintained and synaptogenesis is disrupted between normal synaptic targets or enhanced between non-physiological targets, it can lead to neurological disorders such as epilepsy, autism, mental retardation, and schizophrenia. How a cell distinguishes between the myriad of potential synaptic partners largely remains a mystery in the vertebrate central nervous system. The focus of this proposal is to investigate the basis of synaptic specificity during neural development. The experiments outlined here investigate the hypothesis that neurons in the CNS can differentiate between potential postsynaptic targetes based on cell-cell interactions mediated by cell surface molecules. We will explore this hypothesis by examining the ability of hippocampal dentate gyrus (DG) to preferentially innervate CAS neurons (their appropriate target) in mixed cultures. The goals of this exploratory grant are : (1) to establish a hippocampal microculture system in which synapse preference can be studied and to assess synaptic specificity using immunofluorescence and paired recodings; (2) to develop an expression cloning strategy that can be used to identify molecules that confer synaptic specificity. These findings would then serve as a platform for launching a longer-term project directed at cloning and characterizing genes that contribute to synaptic specificity. ? ?
| Ripley, Beth; Otto, Stefanie; Tiglio, Katie et al. (2011) Regulation of synaptic stability by AMPA receptor reverse signaling. Proc Natl Acad Sci U S A 108:367-72 |
| Williams, Megan E; de Wit, Joris; Ghosh, Anirvan (2010) Molecular mechanisms of synaptic specificity in developing neural circuits. Neuron 68:9-18 |
| de Wit, Joris; Sylwestrak, Emily; O'Sullivan, Matthew L et al. (2009) LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron 64:799-806 |
