Loss of Kirrel family members alters glomerular structure and synapse numbers in the accessory olfactory bulb

Abstract

The accessory olfactory system controls social and sexual behaviours in mice, both of which are critical for their survival. Vomeronasal sensory neuron (VSN) axons form synapses with mitral cell dendrites in glomeruli of the accessory olfactory bulb (AOB). Axons of VSNs expressing the same vomeronasal receptor (VR) converge into multiple glomeruli within spatially conserved regions of the AOB. Here, we have examined the role of the cell adhesion molecule Kirrel2 in the formation of glomeruli within the AOB. We find that Kirrel2 expression is dispensable for early axonal guidance events, such as fasciculation of the vomeronasal tract and segregation of apical and basal VSN axons into the anterior and posterior regions of the AOB, but is necessary for glomeruli formation. Specific ablation of Kirrel2 expression in VSN axons results in the disorganization of the glomerular layer of the posterior AOB and in the formation of fewer and larger glomeruli. Furthermore, simultaneous ablation of Kirrel2 and Kirrel3 expression leads to a loss of morphologically identifiable glomeruli in the AOB, reduced excitatory synapse numbers, and larger presynaptic terminals. Taken together, our results demonstrate that Kirrel2 and Kirrel3 are essential for the formation of glomeruli and suggest they contribute to synaptogenesis in the AOB.

Neph2/Kirrel3 regulates sensory input, motor coordination, and home‐cage activity in rodents

“…33,34 It is imaginable that discrepancies are Data from invertebrates and recent data on mammals provide strong support for the notion that Neph2 is involved in spatiotemporal synapse formation, synaptic transmission levels, and synaptic ultrastructure, particularly in the hippocampus. 12,[35][36][37] It is tempting to surmise that Neph2 exerts similar effects on synapses in the auditory, cerebellar and olfactory circuits. Ultrastructural and electrophysiological approaches are warranted.…”

Kirrel2 is differentially required in populations of olfactory sensory neurons for the targeting of axons in the olfactory bulb

“…To assess whether Kirrel family members are necessary for OSN axonal coalescence, we examined the targeting of five populations of OSN axons that express either tau-lacZ or tau-GFP in mice carrying a targeted deletion of exons 3 and 4 in the Kirrel2 gene. We have previously shown that Kirrel2 protein expression is ablated and that coalescence of vomeronasal sensory neuron axons is altered in these mice (Brignall et al, 2018). We selected these five populations of OSN axons as they target to well-defined regions of the OB (Fig.…”

“…In addition to axonal coalescence, Kirrel family members have been implicated in synapse formation in the hippocampus and accessory olfactory bulb (Shen and Bargmann, 2003; 2004; Martin et al, 2015;Brignall et al, 2018). We therefore assessed the number of excitatory and inhibitory synapses in glomeruli of the OB in Kirrel2 −/− ; Kirrel3 −/− mice.…”

Kirrel3-mediated synapse formation is attenuated by disease-associated missense variants

“…This strongly suggests Kirrel3’s trans-cellular, homophilic interactions are necessary for its function. This is significant because, although prior work indicates that Kirrel3 can undergo homophilic interactions, a functional role of Kirrel3 homophilic interactions at synapses had not been directly tested (Gerk et al, 2005; Serizawa et al, 2006; Martin et al, 2015; Prince et al, 2013; Brignall et al, 2018). Moreover, in the mouse neuromuscular junction, mouse kidney, and at C. elegans synapses, Kirrel3 functions via heterophilic interactions with another Ig-superfamily protein Nephrin-1 (C. elegans Syg-1, Syg-2 respectively) (Shen and Bargmann, 2003; Shen et al, 2004; Gerke et al, 2005; Ding et al, 2007; Chao et al, 2008; Komori et al, 2008; Chia et al, 2014; Özkan et al, 2014).…”