All animals, including humans, must distinguish between behaviorally important events that require attention and other stimuli that do not. Appropriate sensory gating is critical for processing complex information and for remaining alert during simple, but critical tasks. The ability to selectively attend to relevant stimuli is also critical for effective learning. Conversely, inappropriate sensory gating is an important contributor to cognitive dysfunction associated with several psychiatric and neurological disorders as well as chronic pain. Indeed a number of disorders, including schizophrenia, autism and attention deficit hyperactivity disorder, are associated with deficits in sensory gating and attention. Remarkably, nothing is understood about the molecular basis of attention in any system. We have identified a molecular mechanism at sensory neuron synapses that contributes to sensory gating that mediates an attention-like process in a simple model system, the marine invertebrate Aplysia. We have recently made substantial progress in analyzing the mechanism responsible for switching sensory synapses between active and silent states. This bistable synaptic switch involves homosynaptic depression, in which individual release sites are silenced, and burst dependent protection (BDP) from depression, in which a small burst of action potentials prevents the silencing of release sites. Our recent analysis has implicated classical, calcium-activated protein kinase C (PKC Apl-1) in BDP and the small G protein Arf, together with its upstream regulator GEF, in the silencing of release sites. Through this mechanism, animals remain responsive or attentive to salient stimuli that have biological importance and ignore stimuli that are behaviorally irrelevant. Whereas these changes in sensory signaling are non-associative, animals also alter their responsiveness to importance of stimuli during classical conditioning. Conditioning in Aplysia involves associative plasticity at the same sensory synapses. In our analysis of associative synaptic plasticity, we have cloned and characterized 4 adenylyl cyclase (AC) isoforms expressed in the nervous system of Aplysia. We can now test a novel hypothesis about the contribution of one of these ACs to associative plasticity during conditioning.
In Aim 1, we will test the roles of specific Arf GEFs (that catalyze GTP binding to and activating Arf) and specific Arf isoforms in silencing sensory neuron synapses.
In Aim 2 we will use study the precise colocalization of these signaling molecules, including PKC Apl-1, a scaffolding protein PICK1 and Arf GEF, with calcium channels at release sites. To image single molecules we will use novel culture techniques in combination with photoactivatable fluorescent tags.
In Aim 3, we will test a new hypothesis that calcium- inhibited AC also contributes to requirements for stimulus pairing during initiation of synaptic plasticity.
Deficits in attention and in sensory gating are associated with a number of psychiatric and neurological disorders and affect large segments of our population. This research is devoted to understanding molecular mechanisms that gate sensory input to the CNS and contribute to attention. Because nothing is presently known about the molecular mechanism of attention, this work has the potential to lead to development of novel therapeutic approaches for attention disorders.
|Niu, Katelyn Y; Noyes, Nathaniel C; Abrams, Thomas W (2012) Novel approach for generation of low calcium reagents for investigations of heavy metal effects on calcium signaling. J Pharmacol Toxicol Methods 65:122-5|
|Wan, Qin; Jiang, Xue-Ying; Negroiu, Andreea M et al. (2012) Protein kinase C acts as a molecular detector of firing patterns to mediate sensory gating in Aplysia. Nat Neurosci 15:1144-52|
|Lin, Allison H; Cohen, Jonathan E; Wan, Qin et al. (2010) Serotonin stimulation of cAMP-dependent plasticity in Aplysia sensory neurons is mediated by calmodulin-sensitive adenylyl cyclase. Proc Natl Acad Sci U S A 107:15607-12|
|Gover, Tony D; Abrams, Thomas W (2009) Insights into a molecular switch that gates sensory neuron synapses during habituation in Aplysia. Neurobiol Learn Mem 92:155-65|
|Sossin, Wayne S; Abrams, Thomas W (2009) Evolutionary conservation of the signaling proteins upstream of cyclic AMP-dependent kinase and protein kinase C in gastropod mollusks. Brain Behav Evol 74:191-205|
|Dumitriu, Bogdan; Cohen, Jonathan E; Wan, Qin et al. (2006) Serotonin receptor antagonists discriminate between PKA- and PKC-mediated plasticity in aplysia sensory neurons. J Neurophysiol 95:2713-20|
|Cohen, Jonathan E; Onyike, Chiadi U; McElroy, Virginia L et al. (2003) Pharmacological characterization of an adenylyl cyclase-coupled 5-HT receptor in aplysia: comparison with mammalian 5-HT receptors. J Neurophysiol 89:1440-55|
|Gover, Tony D; Jiang, Xue-Ying; Abrams, Thomas W (2002) Persistent, exocytosis-independent silencing of release sites underlies homosynaptic depression at sensory synapses in Aplysia. J Neurosci 22:1942-55|
|Belkin, K J; Abrams, T W (1998) The effect of the neuropeptide FMRFamide on Aplysia californica siphon motoneurons involves multiple ionic currents that vary seasonally. J Exp Biol 201:2225-34|
|Jiang, X Y; Abrams, T W (1998) Use-dependent decline of paired-pulse facilitation at Aplysia sensory neuron synapses suggests a distinct vesicle pool or release mechanism. J Neurosci 18:10310-9|
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