Neuronal activity can modify the efficacy of synaptic transmission. This use-dependent change in synaptic strength may alter information processing in neuronal circuitry and information storage in the brain, and is believed to underlie learning and memory. Much of the effort in this field focuses on the longer-term potentiation and depression at excitatory glutamatergic synapses. However little is known about how inhibitory synaptic transmission is regulated. Inhibitory synapses control the timing and firing patterns of the postsynaptic neuron. Thus a lasting alteration in the strength of inhibitory synaptic transmission can alter the excitability of the postsynaptic neuron changing information processing within a neuronal circuit. Such changes are essential for both the physiological functioning of the brain and for the alterations in neuronal excitability that occur under pathological conditions such as epilepsy. For example enhancing GABA transmission can control epilepsy in many patients, while blocking GABAergic neurotransmission generates seizures. Our recent work shows that repetitive activation of excitatory synaptic inputs in the cerebellum results in a long-lasting increase in the secretion of an inhibitory transmitter, GABA, from a cerebellar interneuron, the stellate cell. This change requires activation of NMDA-type glutamate receptors in stellate cells and enhances the inhibitory synaptic response to GABA in the postsynaptic cell. We propose to study the mechanisms underlying the activity-dependent change in GABA release. In this study, we plan to address the following questions. First, can this form of plasticity also be induced at the stellate/basket cell to Purkinje cell synapse and at the synapse between stellate cells? Second, which subtypes of NMDA receptors are involved in the induction of the lasting increase in GABA release from cerebellar stellate cells? Third, what are the molecular events that are responsible for NMDA receptor-induced enhancement of GABA release? Our investigation of cellular and molecular mechanisms underlying activity-dependent change in inhibitory transmission could contribute to our understanding of cellular mechanisms underlying motor learning and the neurological disorders that is associated with changes in GABAergic transmission. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Talley, Edmund M
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Pennsylvania State University
Schools of Arts and Sciences
University Park
United States
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Bender, Crhistian L; Yang, Qian; Sun, Lu et al. (2016) NH125 reduces the level of CPEB3, an RNA binding protein, to promote synaptic GluA2 expression. Neuropharmacology 101:531-7
Dubois, Christophe J; Lachamp, Philippe M; Sun, Lu et al. (2016) Presynaptic GluN2D receptors detect glutamate spillover and regulate cerebellar GABA release. J Neurophysiol 115:271-85
Savtchouk, Iaroslav; Sun, Lu; Bender, Crhistian L et al. (2016) Topological Regulation of Synaptic AMPA Receptor Expression by the RNA-Binding Protein CPEB3. Cell Rep 17:86-103
Liu, Siqiong June; Savtchouk, Iaroslav (2012) Ca(2+) permeable AMPA receptors switch allegiances: mechanisms and consequences. J Physiol 590:13-20
Dubois, C J; Ramamoorthy, P; Whim, M D et al. (2012) Activation of NPY type 5 receptors induces a long-lasting increase in spontaneous GABA release from cerebellar inhibitory interneurons. J Neurophysiol 107:1655-65
Liu, Yu; Savtchouk, Iaroslav; Acharjee, Shoana et al. (2011) Inhibition of Ca2+-activated large-conductance K+ channel activity alters synaptic AMPA receptor phenotype in mouse cerebellar stellate cells. J Neurophysiol 106:144-52
Savtchouk, Iaroslav; Liu, Siqiong June (2011) Remodeling of synaptic AMPA receptor subtype alters the probability and pattern of action potential firing. J Neurosci 31:501-11
Liu, Yu; Formisano, Luigi; Savtchouk, Iaroslav et al. (2010) A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype. Nat Neurosci 13:223-31
Lachamp, Philippe M; Liu, Yu; Liu, Siqiong June (2009) Glutamatergic modulation of cerebellar interneuron activity is mediated by an enhancement of GABA release and requires protein kinase A/RIM1alpha signaling. J Neurosci 29:381-92
Liu, Siqiong June; Lachamp, Philippe; Liu, Yu et al. (2008) Long-term synaptic plasticity in cerebellar stellate cells. Cerebellum 7:559-62