NA+-ACTIVATED SLO2 K+ CHANNELS ARE ESSENTIAL FOR MEDIATING OLFACTORY ADAPTATION IN VIVO IN DROSOPHILA

Abstract

Olfactory adaptation is essential for maintaining high sensitivity and detecting changes in odorant concentration in our environment. Despite decades of research, the molecular mechanisms that drive this adaptive process remain surprisingly poorly understood. This thesis introduces Na+-activated K+ channels (KNa), encoded by the Slo2 gene, as critical mediators of olfactory adaptation in vivo. We demonstrate that the Drosophila Slo2 channel (dSlo2) is required for normal adaptive behavior: while wild-type flies show desensitized responses after just 2 minutes of odorant pre-exposure, dSlo2-/- null mutants fail to adapt, even at the highest odorant concentrations. We show that loss of dSlo2 disrupts multiple characteristics of olfactory adaptation. In dSlo2-/- mutants, response curves to increasing odorant concentrations fail to display the characteristic shifts observed in wild-type flies following pre-exposure. Adaptation in these mutants only occurs after extending the duration of pre-exposure to 7 minutes, and they also exhibit a prolonged recovery time from the adapted state. We show that dSlo2 is expressed in the cell bodies of both olfactory receptor neurons (ORNs) and projection neurons (PNs), as well as in the distal axonal segment (DAS) of PNs, both critical regions involved with neural excitability. Additionally, targeted down-regulation of dSlo2 in the olfactory receptor neurons (ORNs) and second-order projection neurons (PNs) impairs adaptive responses in vivo. Using the Ca²⁺-dependent reporter, CaLexA, we further show that dSlo2 is required for the dampening of neural activity in both ORNs and PNs following odorant pre-exposure. Finally, we show that the persistent sodium current (INaP) also contributes to olfactory adaptation, and present evidence supporting a model in which the coupling between INaP and dSlo2 currents in ORNs and PNs mediates olfactory adaptation in vivo.