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.
Highlights
IQSEC2 is an X-linked gene that has been previously associated with ASD, ID, and drug-resistant epilepsy[1,2]
In this study, we have employed a battery of social behavioral tests to characterize the deficits in social behavior exhibited by mice with a A350V mutation in the Iqsec[2] gene, a mutation that is associated with epilepsy, ID, and ASD in humans
We demonstrated that a single administration of PF-4778574, a positive allosteric modulator (PAM) modulator of the AMPA type glutamatergic receptors (AMPAR), can rescue some of these deficits
Summary
IQSEC2 is an X-linked gene that has been previously associated with ASD, ID, and drug-resistant epilepsy[1,2]. The IQSEC2 protein contains a catalytic domain (Sec7) characteristic of all GEFS (guanine exchange factors), which promotes GDP exchange for GTP on Arf[6]. It contains an IQ like domain, which has been proposed to bind calmodulin, and thereby modulate the Sec[7] GEF activity of IQSEC25–7. We have further demonstrated that the decrease in surface AMPAR, in the surface GluA2 receptor, is associated with a marked decrease in basal synaptic transmission in the murine model[4].
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