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 ?CaMKII and ?CaMKII plays a critical role in AS, through effects on localization of the splice factor Nova-2. In another subproject involving ?CaMKII, we will clarify how ?CaMKII 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.
Synaptic strength must be regulated in the face of changing levels of input in order to ensure that neurons are able to maintain their output firing within reasonable limits. Homeostatic regulation of action potential configuration and synaptic efficacy works in conjunction with acutely induced Hebbian plasticity to maintain network stability and information flow. This project aim to study the features and mechanisms of adaptation to chronic disuse, and in the process it will advance our understanding of how cells remodel themselves, shedding light on abnormal responses in disease states, including autism spectrum disorders.
|Rosenberg, Evan C; Louik, Jay; Conway, Erin et al. (2017) Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia 58:e96-e100|
|Mullins, Caitlin; Fishell, Gord; Tsien, Richard W (2016) Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops. Neuron 89:1131-1156|
|Li, Boxing; Tadross, Michael R; Tsien, Richard W (2016) Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression. Science 351:863-7|
|Cohen, Samuel M; Ma, Huan; Kuchibhotla, Kishore V et al. (2016) Excitation-Transcription Coupling in Parvalbumin-Positive Interneurons Employs a Novel CaM Kinase-Dependent Pathway Distinct from Excitatory Neurons. Neuron 90:292-307|
|Rink, Timothy J; Tsien, Louis Y; Tsien, Richard W (2016) Roger Yonchien Tsien (1952-2016). Nature 538:172|
|Poo, Mu-Ming; Pignatelli, Michele; Ryan, Tomás J et al. (2016) What is memory? The present state of the engram. BMC Biol 14:40|
|Cohen, Samuel M; Li, Boxing; Tsien, Richard W et al. (2015) Evolutionary and functional perspectives on signaling from neuronal surface to nucleus. Biochem Biophys Res Commun 460:88-99|
|Ma, Huan; Li, Boxing; Tsien, Richard W (2015) Distinct roles of multiple isoforms of CaMKII in signaling to the nucleus. Biochim Biophys Acta 1853:1953-7|
|Peng, Hanchuan; Tang, Jianyong; Xiao, Hang et al. (2014) Virtual finger boosts three-dimensional imaging and microsurgery as well as terabyte volume image visualization and analysis. Nat Commun 5:4342|
|Groth, Rachel D; Tirko, Natasha N; Tsien, Richard W (2014) CaV1.2 calcium channels: just cut out to be regulated? Neuron 82:939-40|
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