Function of astrocytic NMDA receptors

About This Grant

Summary: Astrocytes are active participants in synaptic function and impose their effect by mechanisms such as release of gliotransmitters and synaptogenic molecules involved in synapse formation, maturation and pruning. Astrocytes express a variety of channels and receptors which contribute to their function. Recent investigations using transgenic lines to selectively tag astrocytes and improved techniques for acute dissociation and in situ analysis have revealed robust expression of NMDA receptors in cortical astrocytes. Our recent studies and preliminary results utilizing genetic models, electrophysiology and pharmacological tools demonstrate that cortical and striatal astrocytes express non-canonical GluN2C-containing NMDA receptors. Importantly, these studies demonstrate a critical role of astrocytic NMDA receptors in behavioral control including fear extinction and maintenance of cocaine preference memory. However, there are still large gaps in our understanding of the properties and contribution of astrocytic NMDA receptors to physiology and drug responses. The proposed studies will advance the concept that astrocytic NMDA receptors regulate basal neurotransmission and have unique properties which contribute to NMDA receptor channel blocker effects. Further we hypothesize that astrocytic NMDA receptors regulate the levels of astrocyte-derived synaptogenic factors and their effect on synaptic organization and behavior. Proposed studies will focus on medial prefrontal cortex and dorsal striatum, regions relevant to pathophysiology of neuropsychiatric disorders. Specific Aim 1 will examine the properties and pharmacological characteristics and subunit composition of astrocytic NMDA receptors. In addition, sensitivity of astrocytic NMDA receptors to ketamine and their contribution to the antidepressant effects of ketamine will be tested. Specific Aim 2 will test the effect of modulation of astrocytic NMDA receptors on excitatory neurotransmission in medium spiny neurons. The underlying gliotransmitter mechanism in such effects and its behavioral consequence will be examined. Specific Aim 3 will test the role of astrocytic NMDA receptors in regulating the levels of astrocyte-derived synaptogenic factors and their effect on synaptic organization and cognitive flexibility. To accomplish these aims we will utilize a combination of brain slice electrophysiology, calcium imaging, novel pharmacological tools, in vivo fiber photometry, behavior and in vivo manipulation together with newly developed genetic models for selective manipulation of astrocytic NMDA receptors. The expected outcomes from the proposed studies will identify properties and novel functions of astrocytic NMDA receptors in neural circuits with important implications for neuropsychiatric disorders and NMDA receptor channel blocker effect. Moreover, given the unique subunit composition of astrocytic NMDA receptors, it may be possible to selectively target these receptors to achieve therapeutic effects. Scientific rigor of research design is established by the use of multiple methods and approaches, use of validated models and reagents, consideration of blinding, biological variables and sex in addition to other aspects of experimental design.