Vision dominates the human sensory experience, and the visual cortex in particular is critical for understanding the world around us. During development, molecular and cellular processes such as synapse formation and refinement shape the circuitry underlying the appropriate function of the visual cortex. Therefore, a clear understanding of the mechanisms that support visual system development would facilitate our ability to address neurodevelopmental disorders that impair visual perception. The work proposed herein will provide an important link between the molecular mechanisms of synaptic development and the emergence of specific functional response properties in the primary visual cortex of the awake mouse.
In specific aim 1, I will determine the time-course for the emergence and refinement of several basic receptive field (RF) properties in mouse visual cortex from eye opening to the adult. I will measure extracellular unit activity with high-density silicon probes that span several layers of cortex, while optimized visual stimuli are presented to the mouse. From these recordings, I will use recently developed data analysis techniques to quantify the receptive field properties of distinct classes of cells - excitatory, inhibitory, and specific layers - as they evolve over development. Specifically, I will delineate the ontogeny of orientation selectivity (OS), spatial frequency tuning (SF) and response linearity across these distinct cell types. This will constitute the first complete characterization of the development of these RF properties in the awake mouse visual cortex employing electrophysiology;and it will yield novel cell type and layer specific information that will be required for future mechanistic studies by our lab and others.
In specific aim 2, I will delete specific N-methyl-D-Aspartate receptor (NMDAR) subunits, NR2B or NR2A, from a targeted class of cells where OS first arises in the visual system. Differential expression of these subunits relate to specific developmental phases of visual system development. Therefore, I will test the hypothesis that NR2B and NR2A differentially underlie the establishment and subsequent refinement, respectively, of several RF properties in visual cortex (V1). I will specifically measure the RF properties outlined above at key time-points in development in mice where NR2B or NR2A has been deleted from a specific excitatory cell population that densely occupies layer IV of visual cortex. This integrative approach will significantly impact our understanding of the mechanisms that underlie the development of function in the visual system. Specifically, our targeted studies will add unprecedented mechanistic knowledge of where and when NMDAR mediated activity is required for the establishment and refinement of V1 response properties over early development.
This work will significantly enhance our understanding of the genetic pathways that shape mammalian visual system function during distinct phases of development. Several neurodevelopmental disorders such as Austim Spectrum Disorder, schizophrenia and developmental dyslexia are co-morbid with specific deficits in visual processing. Thus, the work proposed here may significantly enhance our understanding of which classes of genetic changes may lead to the sensory processing deficits associated with neurodevelopmental disorders.