Learning requires the extraction of salient information from a continuously changing environment in order foran animal to generate appropriate cognitive and behavioral adaptations. Inducible transcription factors (ITFs)are a class of immediate early genes that support learning and memory by converting transient molecularsignals into long-lasting changes in cellular function. For many ITFs, a mechanistic understanding of how theyalter cellular physiology remains poorly defined. A recent and notable exception is the transcription factorNpas4. Npas4 is undetectable in quiescent neurons, but is highly expressed in response to elevated excitatoryactivity and the associated calcium influx. Once expressed, Npas4 triggers a gene expression program thatultimately recruits inhibitory synapses to the soma and destabilizes those that form in the dendrites.Consequently, Npas4 recalibrates the balance between excitation and inhibition (E-I) within specific domains ofthe pyramidal neuron, simultaneously gating action potential output while also creating a dendritic environmentthat is more permissive for plasticity. In spite of this progress, it is not known if Npas4 regulates inhibitorysynapses specifically within the domain from which the excitatory signals originate or if Npas4 regulatesdistinct sets of genes in response to different types of excitatory activity. This proposal uses electrophysiology,two-photon glutamate uncaging, immunocytochemistry, and genomic techniques to explore the molecularmechanisms that control Npas4 expression and gene regulation. We show that Npas4 is locally translated inthe dendrites of CA1 pyramidal neurons of the mouse hippocampus. We will define the nature of the excitatoryactivity that induces dendritic Npas4 and explore signaling pathways that transduce synaptic activity to Npas4translation. The results of this work will reveal fundamental neurobiology that underlies E-I regulation and mayinspire novel treatment strategies for disorders that stem from dysregulation of E-I balance.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
