Understanding how neurons interact to create functional circuits can advance our conceptualization of a diverse array of neurological disorders-from autism and schizophrenia, to amblyopia. By delving into the machinery that regulates synaptic modifications, in the developing cortex, the underlying properties that shape connections between neurons can be delineated. Towards this aim, I will examine the evolving role of NMDA-type glutamate receptors (NMDARs) in synaptic plasticity. Over the course of development, synaptic NMDARs undergo a dramatic activity-dependent change in subunit composition, going from being primarily NR2B-type, to increasingly NR2A-type, with maturity. Interestingly, this change in syna ptic subunit composition correlates with developmental changes in the properties of synaptic plasticity. To discriminate subunit-specific functions, I will take advantage of the murine primary visual cortex, which not only undergoes this subunit transition, but is also heavily sculpted by NMDAR-dependent plasticity. Using two complementary approaches, the research objectives outlined in this proposal will be the first to clearly reveal how specific NMDAR subtypes shape synaptic malleability and underlying synaptic characteristics. First, I will use a combination of pharmacology and transgenic mice to address how NR2A- and NR2B-type NMDARs contribute to synaptic plasticity at distinct developmental time points. Then, I will genetically manipulate NMDAR subunit expression in discrete neuronal subpopulations, using a well-established cortical electroporation protocol. Because this innovative technique allows subsets of neurons to be genetically modified, in a wild-type background, it limits the potential for compensatory mechanisms and, importantly, it provides a novel method to parse apart the function of NR2A- and NR2B-type NMDARs. By performing paired electrophysiological recordings, this work will be the first to clearly delineate the pre- and postsynaptic function of specific NMDAR subunits. This work will also elucidate the role of NR2A and NR2B-type NMDARs in: (1) synaptic plasticity, (2) synaptic connectivity, (3) probability of neurotransmitter release, and (4) neuronal firing properties. These research objectives are particularly important because, while NMDARs are known to play a vital role in sculpting neural circuitry, little is definitively known about the unique contributions of particular NMDAR subtypes. By understanding how changes in NMDAR subunit composition contribute to alterations in synaptic function, throughout development and into maturity, we will be better positioned to develop age-appropriate biomolecular and behavioral interventions to alleviate the symptoms of cortical dysfunction.
| Charrier, Cecile; Joshi, Kaumudi; Coutinho-Budd, Jaeda et al. (2012) Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell 149:923-35 |
