Central Rhythmogenesis and Behavior

Seattle Children'S Hospital, Seattle WA

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Our project seeks to determine mechanisms and functions of electrical synapse plasticity (ESP) induced by NMDA receptor (NMDAR) activation in mammalian brain. ESP induced by NMDAR activation that strengthens electrotonic coupling was observed in a fish cranial nerve synapse and in retina and recently in the mammalian inferior olive (IO) by our group, suggesting a general mechanism. The IO is an excellent system to study ESP because interneuronal communication in the IO occurs only by electrical synapses and because the IO has well-defined roles in behavioral adaptations, such as during vestibulo-ocular reflex adaptation and eyeblink conditioning (EBC). A significant challenge is to determine whether strengthening ESP synchronizes in vivo network activity to modulate behavior. Two mechanisms are involved in strengthening ESP in the IO: 1) it requires stimulation of CaMKII; and 2) it occurs within glomeruli of dendritic spines in which NMDARs are in close proximity to gap junctions. Thus, the science in this application addresses 2 important questions: 1) is there a role for NMDA-receptor stimulation of CaMKII in the IO for in vivo activity coherence underlain by ESP to influence behavior?; 2) what protein interactions in IO neurons underlie NMDAR-mediated ESP? Our experiments will determine: 1) whether impairing ESP as measured in vitro reduces activity coherence in the in vivo IO; 2) whether impairing ESP within the IO impairs the adaptive timing of movement measured by eyeblink conditioning; 3) how ESP changes the protein interactome of connexin36; and 4) whether scaffolding proteins implicated in the structural relationship between connexin36 and the NMDAR are necessary for ESP. Successful completion of the project will point to new processes that contribute to optimal brain function whose disruption may contribute to brain disease.