An ErbB4-Positive Neuronal Network in the Olfactory Bulb for Olfaction.

Olfactory information is relayed and processed in the olfactory bulb (OB). Mitral cells (MCs), the principal output excitatory neurons of the OB, are controlled by multiple types of interneurons. However, mechanisms that regulate the activity of OB interneurons are not well understood. We provide evidence that the transmembrane tyrosine kinase ErbB4 is selectively expressed in subsets of OB inhibitory neurons in both male and female mice. ErbB4-positive (ErbB4+) neurons are mainly located in the glomerular layer (GL) and granule cell layer (GCL) and do not express previously defined markers. Optogenetic activation of GL-ErbB4+ neurons promotes theta oscillation, whereas activation of those in the GCL generates gamma oscillations. Stimulation of OB slices with NRG1, a ligand that activates ErbB4, increases GABA transmission onto MCs, suggesting a role of OB NRG1-ErbB4 signaling in olfaction. In accord, ErbB4 mutant mice or acute inhibition of ErbB4 by a chemical genetic approach diminishes GABA transmission, reduces bulbar local field potential (LFP) power, increases the threshold of olfactory sensitivity, and impairs odor discrimination. Together these results identified a bulbar inhibitory network of ErbB4+ neurons for olfaction. Considering both NRG1 and ErbB4 are susceptibility genes for neuropsychiatric disorders, our study provides insight into pathological mechanisms of olfactory malfunctions in these disorders.Significance Statement:This study demonstrates ErbB4+ neurons are a new subset of OB inhibitory neurons in the GL and GCL that innervate MCs and ErbB4- cells. They regulate olfaction by controlling local synchrony and distinct oscillations. ErbB4 inhibition diminishes GABA transmission, reduces bulbar local field potential (LFP) power, increases the threshold of olfactory sensitivity, and impairs odor discrimination. Our results provide insight into pathophysiological mechanism of olfaction deficits in brain disorders associated with NRG1 or ErbB4 mutations.