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

Abstract

Adhesion molecules of the immunoglobulin superfamily (IgSF) are essential for neuronal synapse development across evolution and control various aspects of synapse formation and maturation. Neph2, also known as Kirrel3, is an IgSF adhesion molecule implicated in synapse formation, synaptic transmission and ultrastructure. In humans, defects in the NEPH2 gene have been associated with neurodevelopmental disorders such as Jacobsen syndrome, intellectual disability, and autism-spectrum disorders. However, the precise role in development and function of the nervous system is still unclear. Here, we present the histomorphological and phenotypical analysis of a constitutive Neph2-knockout mouse line. Knockout mice display defects in auditory sensory processing, motor skills, and hyperactivity in the home-cage analysis. Olfactory, memory and metabolic testing did not differ from controls. Despite the wide-spread expression of Neph2 in various brain areas, no gross anatomic defects could be observed. Neph2 protein could be located at the cerebellar pinceaux. It interacted with the pinceau core component neurofascin and other synaptic proteins thus suggesting a possible role in cerebellar synapse formation and circuit assembly. Our results suggest that Neph2/Kirrel3 acts on the synaptic ultrastructural level and neuronal wiring rather than on ontogenetic events affecting macroscopic structure. Neph2-knockout mice may provide a valuable rodent model for research on autism spectrum diseases and neurodevelopmental disorders.

Home-cage monitoring ascertains signatures of ictal and interictal behavior in mouse models of generalized seizures

“…Nocturnal home-cage hypoactivity that we observed in all three models (repeated PTZ, DBA/2J and Scn1a +/- mice) is itself etiologically nonspecific. Similar observations have been made in some [53–55] but not all [64, 65] mouse autism models, following social defeat stress [66] and also in aged mice [67]. Indeed, wide variations in spontaneous home-cage activity and wheel-running exist amongst genetically diverse inbred strains of mice [28, 62].…”

Major oscillations in spontaneous home-cage activity in C57BL/6 mice housed under constant conditions

“…The aspiration to obtain cumulative records of laboratory animal behaviors in a "non-intrusive home-cage like style" dates back more than a century (for an historical re-collection see 33 ) but was until recently restricted to a limited set of tools like the running wheel integrated in the home cage (served critically for the understanding of the circadian rhythm in small rodents). Over the past few years a number of techniques 3,7,[34][35][36][37][38][39][40][41][42][43][44][45][46] have become available for automated non-intrusive 24/7 monitoring of in-cage activity 47 of single housed 7,35,40,44 and group housed 8,34,36,37,43,45,48,49 small rodents. Recently we analyzed data of cage floor activity of group-held mice using a DVC system to characterize daily rhythms of spontaneous in-cage activity and impact by husbandry routines 8 .…”

Molecular and Structural Basis of Olfactory Sensory Neuron Coalescence by Kirrel Receptors

“…and Kirrel3 have chemically incompatible interface sequences similar to mouse Kirrels and that extant jawed fish Kirrel sequences also follow these patterns, Kirrel specialization must have appeared early in gnathostomes and before the rise of distinct accessory olfactory systems and several expansions in olfactory receptor gene families (Bear et al, 2016;Poncelet and Shimeld, 2020 (Brignall et al, 2018;Nakashima et al, 2019;Prince et al, 2013;Vaddadi et al, 2019), and Kirrel3 knockout mice show behavioral abnormalities similar to those in autistic patients, including defects in social responses, auditory sensory processing and communication, and repetitive behaviors (Hisaoka et al, 2018;Völker et al, 2018), in addition to loss of male-male aggression likely as a result of miswiring in the AOB (Prince et al, 2013). Furthermore, several mutations in human autism and intellectual disability patients were identified (see Taylor et al., 2020 for a list).…”