Molecular mechanisms of activity-dependent changes in neuronal connectivity

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DESCRIPTION (provided by applicant): During development and throughout adulthood, the nervous system transforms sensory experience from the environment into changes in neuronal activity which, in turn, cause long-lasting alterations in synaptic connections and dendritic arborization. Disruption to this process can result in long-term undesirable neurological consequences. For example, altered synapse number and functional plasticity responses are hallmarks of a number of mental health disorders including depression and schizophrenia [1-3]. Despite the importance of activity-dependent processes in shaping neuronal architecture, little is known about the molecular mechanisms by which changes in neuronal excitability are translated into altered connectivity. Using an RNAi-based approach in cultured neurons, we identified the GTPase Rem2 as a novel regulator of excitatory synapse development [4, 5]. We have also demonstrated that Rem2 is a novel immediate early gene whose transcription is rapidly up-regulated in response to calcium influx via neuronal depolarization [6]. Thus, Rem2 may represent a key molecule through which external stimuli mediate direct effects on neuronal connectivity. To test this hypothesis in the intact nervous system of a vertebrate model organism, I propose to knockdown Rem2 in pyramidal neurons in rodent visual cortex and perform in vivo two-photon imaging of the synaptic contacts and overall circuit plasticity of these neurons while modulating visual experience. This experience-dependent in vivo approach to identify the role of Rem2 in activity-dependent neural circuit development provides an excellent opportunity to increase our understanding of genetically encoded, activity- dependent neural circuitry. Through a unique collaboration between mentors with expertise in in vivo circuit analysis, synapse development, and the molecular biology of gene regulation, I will become an expert in an impressive array of experimental techniques which will allow me to probe the function of other activity- regulated genes in the intact nervous system in the future.