Glomeruli are the structures around which neurons are organized in the olfactory bulb. Each glomerulus carries information about a single odorant receptor in the nose, and has a specific population of glutamatergic mitral cells (MCs) and tufted cells (TCs) associated with it. The broad objective of this proposal is to build on provocative recent results from a variety of labs, including our own, pertaining to the cellular connectivity within a glomerulus. These studies suggest that most signaling between olfactory sensory neurons (OSNs) and MCs occurs through a multi-step path involving intermediary glutamatergic TCs (OSN-to-TC-to-MC), differing from the canonical model of direct OSN-to-MC excitation. In addition, glutamatergic signals from TCs are unusual, being mediated by long-range extrasynaptic transmission. These results are however controversial, as limited ultrastructural data suggest that OSNs are at least capable of making direct morphological contacts on MCs. In this application, we propose in Aim 1 to apply new approaches, including quantitative ultrastructural analyses, to establish whether the multi-step path is indeed the dominant signaling mechanism between OSNs and MCs.
Aims 2 and 3 will then examine possible functional implications of a multi-step path for MCs using electrophysiological recordings in brain slices and awake behaving mice. The extrasynaptic nature of glutamate signaling from TCs, in particular, predicts that excitation of MCs should be highly non-linear, reflecting the accumulation of glutamate. For odor responses, this could, mean, for example, that MC responses to different odors are exceptionally sparse and display a steep dependence on odor concentration. A key tool in our functional studies will be connexin-36 knockout mice. Because OSN signaling onto MCs in these mice appears to be converted from multi-step to monosynaptic, they provide a potentially direct way to assess whether the multi-step activation path for MCs is causally related to specific functional properties. Taken together, our studies wil lead to important new information about the relationship between the structure and function of an olfactory circuit.
In humans, deficits in the sense of smell are encountered in many neurological disorders such as Alzheimer's disease and schizophrenia. Our studies of fundamental circuit mechanisms in the olfactory bulb will provide the basis for understanding specific disease-associated olfactory deficits and also potential treatments.
|Pouille, Frederic; Schoppa, Nathan E (2018) Cannabinoid Receptors Modulate Excitation of an Olfactory Bulb Local Circuit by Cortical Feedback. Front Cell Neurosci 12:47|
|Pouille, Frederic; McTavish, Thomas S; Hunter, Lawrence E et al. (2017) Intraglomerular gap junctions enhance interglomerular synchrony in a sparsely connected olfactory bulb network. J Physiol 595:5965-5986|
|Bourne, Jennifer N; Schoppa, Nathan E (2017) Three-dimensional synaptic analyses of mitral cell and external tufted cell dendrites in rat olfactory bulb glomeruli. J Comp Neurol 525:592-609|
|Shen, Chong; Rathore, Shailendra S; Yu, Haijia et al. (2015) The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis. Nat Commun 6:8852|
|Zak, Joseph D; Whitesell, Jennifer D; Schoppa, Nathan E (2015) Metabotropic glutamate receptors promote disinhibition of olfactory bulb glomeruli that scales with input strength. J Neurophysiol 113:1907-20|
|Sheridan, D C; Hughes, A R; Erdélyi, F et al. (2014) Matching of feedback inhibition with excitation ensures fidelity of information flow in the anterior piriform cortex. Neuroscience 275:519-30|
|Whitesell, Jennifer D; Sorensen, Kyle A; Jarvie, Brooke C et al. (2013) Interglomerular lateral inhibition targeted on external tufted cells in the olfactory bulb. J Neurosci 33:1552-63|
|Gire, David H; Franks, Kevin M; Zak, Joseph D et al. (2012) Mitral cells in the olfactory bulb are mainly excited through a multistep signaling path. J Neurosci 32:2964-75|
|Gire, David H; Schoppa, Nathan E (2009) Control of on/off glomerular signaling by a local GABAergic microcircuit in the olfactory bulb. J Neurosci 29:13454-64|
|Luna, Victor M; Schoppa, Nathan E (2008) GABAergic circuits control input-spike coupling in the piriform cortex. J Neurosci 28:8851-9|
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