The integration of information in the mammalian CNS depends on precise timing of synaptic activity. The temporal integration of synaptic responses is the basis of most forms of synaptic plasticity and underlies the ability of brain regions to execute system functions such as sensory discrimination, learning and memory, and motor programs. 'Coincidence detection' as a mechanism of plasticity at excitatory synapses mediated by glutamate is a well-known example of the fundamental importance of synaptic timing. However, there is also strong evidence to suggest that GABAergic inhibition provides more than a brake on excitation, but is fundamental to shaping the output of neuronal circuits. For example, the activity of single inhibitory hippocampal neurons can synchronize the activity of hundreds of principal neurons. Such integration is determined by three fundamental elements: the strength as well as the duration of individual synaptic responses; the connectivity of synapses within the network; and the excitable properties of neurons. While each of these elements has been intensively investigated in isolation, few experimental systems bridge the gap between cellular mechanisms and the network response. Models of neuronal networks have often viewed synaptic responses as short-lived, lasting at most a few tens of milliseconds. However, the cellular response at central synapses can persist much longer, either due to the kinetics of the underlying postsynaptic ion channels or to the escape of transmitter from the synaptic cleft. Such mechanisms are thus prime candidates for controlling synaptic integration. In this proposal, we use two synaptic circuits to examine how the duration of synaptic inhibition may contribute to the function of neuronal networks.
In Aims 1 -3 we will examine the determinants of the long-lasting GABAA-mediated inhibition at dendrodendritic synapses in the olfactory bulb. The unique circuitry of the bulb provides an ideal model system to examine the role of lateral inhibition in shaping sensory information. We hypothesize that the duration of the GABAergic inhibition shapes reciprocal and lateral inhibition, the main processing function of the olfactory bulb. Our long-term goal is to understand how the properties of individual synapses provide the substrate for the integrative functions of this network.
In Aim 4, we will develop new kinetic approaches to examine two aspects of long-lasting inhibition, the role of slow desensitization and spillover of free GABA, on synaptic function in hippocampal neurons. We will use single synapses in microdot cultures as well as brain slices. These experiments are expected to provide fundamental insights into the operation of synaptic networks, and have direct implications for normal information processing in the brain as well as the pathophysiology of sensory deficits, anxiety, memory loss, dementia and epilepsy.
|Tovar, Kenneth R; Westbrook, Gary L (2017) Modulating synaptic NMDA receptors. Neuropharmacology 112:29-33|
|Vaaga, Christopher E; Westbrook, Gary L (2016) Parallel processing of afferent olfactory sensory information. J Physiol 594:6715-6732|
|Vaaga, Christopher E; Borisovska, Maria; Westbrook, Gary L (2014) Dual-transmitter neurons: functional implications of co-release and co-transmission. Curr Opin Neurobiol 29:25-32|
|Vaaga, Christopher E; Tovar, Kenneth R; Westbrook, Gary L (2014) The IGF-derived tripeptide Gly-Pro-Glu is a weak NMDA receptor agonist. J Neurophysiol 112:1241-5|
|Tovar, Kenneth R; McGinley, Matthew J; Westbrook, Gary L (2013) Triheteromeric NMDA receptors at hippocampal synapses. J Neurosci 33:9150-60|
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|Tovar, Kenneth R; Westbrook, Gary L (2012) Amino-terminal ligands prolong NMDA Receptor-mediated EPSCs. J Neurosci 32:8065-73|
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|Borisovska, Maria; McGinley, Matthew J; Bensen, AeSoon et al. (2011) Loss of olfactory cell adhesion molecule reduces the synchrony of mitral cell activity in olfactory glomeruli. J Physiol 589:1927-41|
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