Electrical Synapses and Network Signaling

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DESCRIPTION (provided by applicant): Noradrenaline released from the locus coeruleus powerfully controls the electrical activity of the hippocampus and has been implicated in the regulation of attention, memory processes, and in the prevention of epileptiform activity. Specifically, the preferential synaptic targets of noradrenaline in the hippocampus are GABAergic interneurons, which express the gap junction protein Connexin 36, and are organized in electrically coupled networks. Gap junctions shape GABAergic network activity and integration by synchronizing firing and boosting the propagation of subthreshold postsynaptic potentials. The broad aim of this project is the identification of molecular mechanisms of gap junction modulation in GABAergic networks of the hippocampus. We will test the overarching hypothesis that noradrenergic regulation of electrical coupling is mediated by specific second messengers and protein kinases, and controls network dynamics. Despite the abundance of studies investigating noradrenergic control of neuronal intrinsic properties, modulation of electrical synapses is a virtually unexplored field in mammalian cortical GABAergic circuits. However, the control of the strength of interneuronal coupling could impact hippocampal integration and network dynamics that are at the basis of essential cognitive functions. In addition, unraveling new mechanisms of gap junction regulation could suggest new therapeutic strategies against epilepsy. Methodologically, we will take advantage of a combination of electrophysiology in vitro, anatomy, and pharmacology applied to wild type and Connexin 36-knock out animals. PUBLIC HEALTH RELEVANCE Although neurons communicate by using both chemical and electrical synapses, most of the current pharmacological therapy of brain disease is based on drugs modulating chemical synaptic transmission. The work proposed here will study mechanisms of neuronal communication based on electrical synapses, and their regulation. Discovering new mechanisms of synaptic modulation could reveal additional targets for therapeutic intervention that could be exploited by a new generation of drugs, which is currently under development and testing.