Learning requires the extraction of salient information from a continuously changing environment in order for an 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 molecular signals into long-lasting changes in cellular function. For many ITFs, a mechanistic understanding of how they alter cellular physiology remains poorly defined. A recent and notable exception is the transcription factor Npas4. Npas4 is undetectable in quiescent neurons, but is highly expressed in response to elevated excitatory activity and the associated calcium influx. Once expressed, Npas4 triggers a gene expression program that ultimately 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 of the pyramidal neuron, simultaneously gating action potential output while also creating a dendritic environment that is more permissive for plasticity. In spite of this progress, it is not known if Npas4 regulates inhibitory synapses specifically within the domain from which the excitatory signals originate or if Npas4 regulates distinct 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 molecular mechanisms that control Npas4 expression and gene regulation. We show that Npas4 is locally translated in the dendrites of CA1 pyramidal neurons of the mouse hippocampus. We will define the nature of the excitatory activity that induces dendritic Npas4 and explore signaling pathways that transduce synaptic activity to Npas4 translation. The results of this work will reveal fundamental neurobiology that underlies E-I regulation and may inspire novel treatment strategies for disorders that stem from dysregulation of E-I balance.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that can arise from dysregulation of the balance between neuronal excitation and inhibition (E-I). The transcription factor Npas4 is expressed in response to elevated excitation and regulates inhibitory synapses that converge onto the active neuron, thus directly regulating E-I balance. The goal of this proposal is to determine the specific signals and regulatory elements that govern Npas4 expression. These findings will shed new light on the complex biology associated with ASD.
