Abstract
The role of insulin pathways in olfaction are of significant interest with the widespread pathology of Diabetes mellitus and its associated metabolic and neuronal co-morbidities. Previous experiments have been conducted examining insulin function in vitro, focusing on the modulation of the dominant Shaker channel Kv1.3 in the olfactory bulb (OB). The insulin receptor (IR) kinase is expressed at high levels in the OB, where it suppresses the Kv1.3 via tyrosine phosphorylation of critical N-and C-terminal residues. IR as well as other tyrosine kinases likely evoke Kv1.3 current suppression via tyrosine phosphorylation-dependent channel subunit multilerization. The adaptor protein post-synaptic density 95 (PSD-95) disrupts insulin-evoked Kv1.3 current suppression by inhibiting channel tyrosine phosphorylation and subunit miltimerization, demonstrating a role for adaptor proteins as indirect OB ion channel and hormone modulators. Kv1.3 co-immunoprecipitates and co-localizes with PSD-95 and IR in the OB, demonstrating a scaffolding interaction, participation in insulin signaling and integration in large “Signaling Megaplexes”. However, it is difficult to understand the full scope of insulin function in olfaction because of a large data gap between insulin-evoked biochemical and behavioral effects in situ. Therefore seven day chronic intranasal insulin delivery (IND) in awake mice was optimized to ascertain the biochemical and behavioral effects of insulin in the OB. IND evoked robust phosphorylation of Kv1.3 in the OB, as well as increased channel protein-protein interactions with IR and PSD-95 and alteration of Signaling Megaplexes. IND increased short- and long-term object memory recognition in mice, evoked anxiolytic behavior, increased odor discrimination, but did not affect odorant threshold. Thus, insulin-evoked ion channel modulation and alteration of scaffolding interactions appear to affect olfactory-related biochemistry and behaviors, suggesting a mechanism for a metabolic hormone to influence olfaction.
|
