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.
The project examines electrical synapses in mammalian brain. Electrical synapses complement the function of chemical synapses and are now known to be modulated by chemical synapses, providing a novel mechanism for brain plasticity and learning. Our project will study mechanisms by which the NMDA receptor controls plasticity of electrical synapses in order to more fully understand the processes that underlie optimal brain function and whose disruption may contribute to brain disease.
| Turecek, Josef; Han, Victor Z; Cuzon Carlson, Verginia C et al. (2016) Electrical Coupling and Synchronized Subthreshold Oscillations in the Inferior Olive of the Rhesus Macaque. J Neurosci 36:6497-502 |
| Turecek, Josef; Yuen, Genevieve S; Han, Victor Z et al. (2014) NMDA receptor activation strengthens weak electrical coupling in mammalian brain. Neuron 81:1375-1388 |
| Oristaglio, J; Hyman West, S; Ghaffari, M et al. (2013) Children with autism spectrum disorders show abnormal conditioned response timing on delay, but not trace, eyeblink conditioning. Neuroscience 248:708-18 |
| Fatemi, S Hossein; Aldinger, Kimberly A; Ashwood, Paul et al. (2012) Consensus paper: pathological role of the cerebellum in autism. Cerebellum 11:777-807 |
| Vianney-Rodrigues, Paulo; Iancu, Ovidiu D; Welsh, John P (2011) Gamma oscillations in the auditory cortex of awake rats. Eur J Neurosci 33:119-29 |
| Welsh, John P; Han, Victor Z; Rossi, David J et al. (2011) Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence. Proc Natl Acad Sci U S A 108:10314-9 |
| Placantonakis, Dimitris G; Bukovsky, Anatoly A; Aicher, Sue A et al. (2006) Continuous electrical oscillations emerge from a coupled network: a study of the inferior olive using lentiviral knockdown of connexin36. J Neurosci 26:5008-16 |
| Welsh, John P; Yamaguchi, Hidetoshi; Zeng, Xiao-Hui et al. (2005) Normal motor learning during pharmacological prevention of Purkinje cell long-term depression. Proc Natl Acad Sci U S A 102:17166-71 |
| Welsh, John P; Ahn, Edward S; Placantonakis, Dimitris G (2005) Is autism due to brain desynchronization? Int J Dev Neurosci 23:253-63 |
| Placantonakis, Dimitris G; Bukovsky, Anatoly A; Zeng, Xiao-Hui et al. (2004) Fundamental role of inferior olive connexin 36 in muscle coherence during tremor. Proc Natl Acad Sci U S A 101:7164-9 |
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