Neuronal Adaptation and Plasticity after Chronic Disuse



 DESCRIPTION (provided by applicant): Homeostatic regulation of excitability and synaptic efficacy works in conjunction with acutely induced Hebbian plasticity to maintain neuron firing within limits and thus preserve network stability and information flow. There is general agreement that homeostatic synaptic plasticity can be global (uniform scaling across all synapses of a neuron) or local (synaptic strength not uniformly scaled), and can be mediated by diverse molecular mechanisms. Interestingly, dysfunctional homeostasis has been invoked as a basis for brain diseases such as autism spectrum disorders (ASD). Despite major effort, the molecular underpinnings of diverse forms of homeostatic adaptation are still not very clear. In this project, we will examine various aspects of neuronal homeostasis with relevance to neuropsychiatric disorders. The first question is how neuronal inactivity initiates local signaling near postsynaptic CaV1 channels and causes propagation of signals to the nucleus to regulate alternative mRNA splicing (AS) and thus affect spike duration. We will find out how one ASD-related gene (CACNA1C, L-type Ca2+ channel subunit) controls the expression of another (KCNMA1, BK channel subunit). Our preliminary data suggest that signaling to the nucleus via βCaMKII and γCaMKII plays a critical role in AS, through effects on localization of the splice factor Nova-2. In another subproject involving βCaMKII, we will clarify how βCaMKII affects postsynaptic glutamate receptor composition, and a striking switchover from Ca2+- impermeable to Ca2+-permeable AMPA receptors. Coordination between changes in postsynaptic receptors and presynaptic function will also be investigated, with a focus on retrograde signaling molecules such as BDNF. We will extend our studies to homeostasis at the level of recurrent circuits in cultured hippocampal slices, using an all-optical approach to visualize a hypothesized reallocation of presynaptic weights following inactivity. Finally, we will explore why inactivity-driven BK splicing is more severe in neurons derived from a mouse model of Timothy Syndrome, a rare form of ASD, thereby connecting malfunction of genes to cellular effects of relevance to disease states. Taken together, our studies will clarify the homeostatic functions of key signaling proteins and offer a fresh approach to the possible links between the abnormal homeostatic adaptation and neuronal disorders like ASD.