A role for ephrins-A2, -A3, & -A5 in excitatory synaptic development and function

Georgetown University, Washington DC

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Abstract

DESCRIPTION (provided by applicant): Complex thoughts and movements require the integration of topographically organized cortical information about sensory, motor, and motivational states. These integrated networks involve corticostriatal synapses on dendritic spines of medium spiny projection neurons (MSNs), which are organized into unique compartments within the striatum. Epigenetic and genetic factors that alter the expression of molecules regulating the normal development of striatal neuronal compartments, corticostriatal afferent organization, or synaptic physiology could be involved in the etiology of the neuropsychiatric disorders associated with the striatum. Thus, my proposal aims are to identify a role for members of one molecular family of cell-surface signaling molecules, the A-class ephrins, in the proper development of striatal circuitry. Eph/ephrins are compelling candidate molecules that could participate in developmental events necessary to regulate the proper formation of striatal compartments and corticostriatal synaptogenesis due to their ability to regulate neuronal migration, axonal pathway topography and dendritic morphology, as well as modulate synaptic function via glutamate receptor trafficking. Mice with genetic deletions of ephrins-A2, -A3, and -A5 have disorganized striatal sub compartments and display differences in locomotor activity levels, repetitive facial grooming, and perseverance of inappropriate motor strategies during learning. These observations suggest that certain A- ephrins could differentially affect anatomical and physiological features essential for normal behaviors associated with corticostriatal function. It is currently unknown whether changes in the relative expression of ephrin-A2, -A3, and/or -A5 affect synaptic development or neurotransmission at corticostriatal synapses. Therefore, this research will include electrophysiology studies to examine changes in glutamate receptor trafficking and stereological studies of morphology to measure changes in dendrites of medium spiny neurons (MSNs), the main projection neurons in the striatum. Two subtypes of MSNs are distinguished by dopamine receptor D1 or D2 expression and these form the direct and indirect basal ganglia pathways, respectively. As many neuropsychiatric disorders linked to striatal dysfunction are thought to involve a functional imbalance between these two pathways, it is of particular interest to understand the effect that changes in the relative proportion of A-ephrins might have on excitatory physiology in these two populations of MSNs. This proposal entails use of unique transgenic mice expressing fluorescent marker proteins in each MSN subtype in combination with genetic deletions of ephrins-A2, -A3, and/or -A5. This model permits assessment of glutamate receptor activity and dendritic morphology in D1+ vs. D2+ MSNs. The guiding hypothesis is that changes in glutamatergic synaptic transmission and dendritic morphology will occur differentially in D1+ versus D2+ MSNs of mice with specific deletions of ephrins-A2/3/5. These studies will thus evaluate genetic factors that could contribute at multiple levels to the etiology of developmental neuropsychiatric disorders.