Precision medicine for the rescue of specific impairments in social behavior associated with the A350VIqsec2mutation

Abstract

In this study we tested the hypothesis that precision medicine guided therapy targeting 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. 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 PF-4778574. We conclude that social behavior deficits associated with the A350V Iqsec2 mutation may be rescued by enhancing AMPAR mediated synaptic transmission.

Structural and functional brain-wide alterations in A350V Iqsec2 mutant mice displaying autistic-like behavior

“…The A350V mouse model was generated using CRISPR technology based on a human de novo mutation 32 and demonstrated a significant reduction in the surface expression of GluA2 AMPA receptors in hippocampal neurons along with increased locomotion activity and abnormal social behavior. Further, a more recent study that thoroughly characterized social behaviors in this model found that A350V mice display deficits in sex preference and emotional state preference behaviors 33 . Collectively, these findings demonstrate that the A350V mouse model manifests some of the abnormalities found in the human condition that inspired the generation of this mouse model.…”