This project will focus on the hypothesis that N-methyl-D-aspartate (NMDA) glutamate receptors and neuronal gap junctions act concertedly to determine the spatio-temporal dynamics of activity within electrically coupled networks in brain. The hypothesis will be tested in the inferior olive, a major afferent of the cerebellum that has the highest density of electrical synapses in the adult brain. Previous work from our laboratory showed that NMDA receptor activation induces high-threshold oscillations in membrane potential in inferior olive neurons and that neuronal gap junctions mediated by connexin36 are critical for the continuity and strength of coherent oscillations in the inferior olive. There are 4 aims.
Aim 1 will determine whether NMDA receptors regulate electrical coherence and rhythm within a coupled network by acting on neuronal gap junctions in vivo.
Aim 2 will determine whether NMDA receptors shape the spatial dynamics of electrical coupling in vitro.
Aim 3 will determine whether there is a correspondence between NMDA receptor upregulation in the inferior olive and hypoxia-induced death of cerebellar neurons.
Aim 4 will determine whether the block of NMDA receptor function in the inferior olive alone, or with neuronal gap junctions, will prevent delayed neuronal death in the cerebellum after hypoxia.
These aims will be carried out with a combination of multielectrode recording, multibeam multiphoton microscopy, and gene transfer to express proteins with dominant-negative effect and RNA inhibitor sequences in the inferior olive. Recently, the upregulation of the NMDA receptor in the inferior olive and the death of Purkinje cells were independently related to sudden infant death syndrome. The research will establish how these clinically-relevant phenomena are related to one another.
The studies proposed in the present application will provide important information about the mechanisms of neuronal oscillation in a specific brain region named the inferior olive, and the potential for pathological activity in that brain area for triggering neuronal death in the cerebellum. The results of these studies will be useful not only for our general understanding of brain function but may be relevant to the sudden infant death syndrome, a tragic result of cumulative hypoxic damage to the brain. The long term goal of these studies is to determine the cell biological and neuronal ensemble mechanisms of normal and pathological oscillations in the brain.
|Turecek, Josef; Yuen, Genevieve S; Han, Victor Z et al. (2014) NMDA receptor activation strengthens weak electrical coupling in mammalian brain. Neuron 81:1375-88|
|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|
|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|
|Johnson, Jennie L; Welsh, John P (2003) Independently movable multielectrode array to record multiple fast-spiking neurons in the cerebral cortex during cognition. Methods 30:64-78|
|Welsh, John P; Yuen, Genevieve; Placantonakis, Dimitris G et al. (2002) Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. Adv Neurol 89:331-59|
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