Pharmacological modulation of AMPA receptors rescues specific impairments in social behavior associated with the A350V Iqsec2 mutation

Abstract

In this study we tested the hypothesis that pharmacological modulation of glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in the Iqsec2 gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in the IQSEC2 gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. Using a battery of social behavioral tasks, we found that A350V Iqsec2 mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with a single dose of PF-4778574. We conclude that social behavior deficits associated with the A350V Iqsec2 mutation may be rescued by enhancing AMPAR mediated synaptic transmission.

Sex-dependent features of social behavior differ between distinct laboratory mouse strains and their mixed offspring

“…SP and SNP tests were conducted on the same day, as previously described (Netser et al, 2019). The SxP test was conducted two days later (see Figure S1A) as previously described (Jabarin et al, 2021). Briefly, it consisted of 15 min habituation to the arena with empty chambers, followed by exposing the subject for 5 min to both novel adult male and female social stimuli located in individual…”

“…We have previously presented a computational experimental system for automatic assessment of murine social discrimination behavior (Netser et al, 2019) and used it to analyze the behavior of C57BL/6J mice in the SP and SNP paradigms (Netser et al, 2017(Netser et al, , 2020. Here, we added a third paradigm of social discrimination, the sex-preference (SxP) paradigm (Jabarin et al, 2021), in order to systematically examine sex-and strain-dependent behavioral parameters in the three most commonly used (estimated by publications, see https://www.labome.com/method/Laboratory-Mice-and-Rats.html) laboratory mouse strains (C57BL/6J, BALB/c, and ICR). Moreover, we characterized the behavior of offspring generated by crossbreeding of C57BL/6J and BALB/c mice.…”

IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex

“…The interaction with a stranger mouse was more robust than with a familiar mouse in the mutant mice in the social novelty preference test [21]. Deficits in sex preference and emotional state preference were also observed in the mutant mice, which were rescued by administration of positive AMPAR modulator PF-4778574 [23].…”

Beyond the three-chamber test: toward a multimodal and objective assessment of social behavior in rodents

“…The 16p11.2 +/− line used to model ASD, as an instance, displayed intact social preference in multiple studies [ 83 , 84 , 88 ], yet exhibited deficits in other behavioral tasks, including sex preference and emission of mating calls [ 39 , 88 ], social recognition memory and habituation [ 83 , 84 ], and the degree of direct social interaction [ 87 ]. Another example is the Iqsec2 A350V line, which showed intact social preference and social novelty preference in the three-chamber test, yet also displayed deficits in sex and emotional state preference [ 73 ].…”

“…Such abilities can be independently hindered regardless of the general social propensity of the tested subjects. Iqsec2 A350V-mutated mice, for example, exhibit deficits in specific social interactions that include emotionally-arousing stimuli [ 73 ]. Therefore, the application of behavioral tests designed for assessing emotion-cognition-related processes might yield greater insight into behavioral deficits related to ASD.…”