In the mammalian CNS rapid excitatory neurotransmission is mediated largely by glutamate acting on synaptic ionotropic AMPA- and NMDA-type glutamate receptors (AMPARs and NMDARs). At CA1 synapses in the hippocampus the strength of this transmission can be regulated by different patterns of neuronal activity. This bidirectional synaptic plasticity is a cellular mechanism for learning and memory. Long-term potentiation (LTP), a model of synaptic plasticity, is mediated in part by Ca2+ activation of CaMKII which phosphorylates several postsynaptic proteins, including AMPARs, to acutely regulate their function. However, molecular mechanisms responsible for trafficking of AMPARs into synapses, a crucial mechanism for LTP, and perhaps changes in their subunit composition to favor Ca2+-permeable AMPARs (CP- AMPARs) are poorly understood. We have preliminary evidence that another class of CaMKs, namely CaM- kinase kinase (CaMKK) and its downstream target CaMKI, may be involved in synaptic trafficking of CP- AMPARs. Furthermore, our studies on developmental formation of spines and synapses in cultured neurons have identified a multiprotein signaling complex that enhances CaMKK/CaMKI phosphorylation of PIX, a Rac guanine-nucleotide exchange factor that promotes spinogenesis through regulation of the actin cytoskeleton. Based on preliminary results, we propose that CaMKI may also be involved in regulating spine density and morphology during structural plasticity that occurs during LTP maintenance and that CP-AMPARs are essential for these structural changes. The main goal of this application is to identify novel signaling pathways involving CaMKK and CaMKI that mediate AMPAR trafficking/recomposition and structural plasticity during synaptic potentiation, probably through modulating the actin cytoskeleton. However, we will also look at possible involvement of CaMKII in these events. This will be a multifaceted investigation that will utilize 1) cultured hippocampal neurons, acute and organotypic cultured hippocampal slices, 2) induction of synaptic potentiation by theta-burst stimulation or treatment with the NMDA receptor co-agonist glycine, 3) pharmacological reagents, transfected dominant-negative and constitutively-active constructs and siRNAs, and 4) electrophysiological and biochemical analyses. Our laboratory has extensive experience with all these approaches and we are in a unique position to undertake this investigation. The cumulative results from these studies will further our understanding of molecular mechanisms underlying synaptic potentiation during paradigms of learning and memory. Furthermore, our studies on signaling pathways that regulate spine morphology and density will have strong clinical implications as several forms of mental retardation (e.g., Down's, Rett, Fragile X and fetal alcohol syndromes) are associated with aberrant spine structures and/or numbers.

Public Health Relevance

These studies will elucidate molecular mechanisms that contribute to synaptic plasticity, a cellular model of learning and memory in the brain. Furthermore, they will identify signaling pathways responsible for formation of calcium-permeable AMPA-type glutamate receptors that are promote cell death in several neuropathologies such as ischemia, stroke, and Alzheimer's disease. Lastly, we will investigate mechanisms for formation of functional dendritic spines, which are abnormal in several forms of mental retardation (e.g., Fragile X, Rett and Down's syndromes).

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Whittemore, Vicky R
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Oregon Health and Science University
Schools of Medicine
United States
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Chen, Yishen; Derkach, Victor A; Smith, Peter A (2016) Loss of Ca(2+)-permeable AMPA receptors in synapses of tonic firing substantia gelatinosa neurons in the chronic constriction injury model of neuropathic pain. Exp Neurol 279:168-177
Fortin, Dale A; Srivastava, Taasin; Dwarakanath, Diya et al. (2012) Brain-derived neurotrophic factor activation of CaM-kinase kinase via transient receptor potential canonical channels induces the translation and synaptic incorporation of GluA1-containing calcium-permeable AMPA receptors. J Neurosci 32:8127-37
Fortin, Dale A; Srivastava, Taasin; Soderling, Thomas R (2012) Structural modulation of dendritic spines during synaptic plasticity. Neuroscientist 18:326-41
Srivastava, Taasin; Fortin, Dale A; Nygaard, Sean et al. (2012) Regulation of neuronal mRNA translation by CaM-kinase I phosphorylation of eIF4GII. J Neurosci 32:5620-30
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Saneyoshi, Takeo; Fortin, Dale A; Soderling, Thomas R (2010) Regulation of spine and synapse formation by activity-dependent intracellular signaling pathways. Curr Opin Neurobiol 20:108-15
Fortin, Dale A; Davare, Monika A; Srivastava, Taasin et al. (2010) Long-term potentiation-dependent spine enlargement requires synaptic Ca2+-permeable AMPA receptors recruited by CaM-kinase I. J Neurosci 30:11565-75
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Pinto, Vitor; Szucs, Peter; Derkach, Victor A et al. (2008) Monosynaptic convergence of C- and Adelta-afferent fibres from different segmental dorsal roots on to single substantia gelatinosa neurones in the rat spinal cord. J Physiol 586:4165-77

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