IQSEC2, also known as BRAG1, is a guanine nucleotide exchange factor (GEF) highly enriched in synapses. It plays a crucial role in neuronal development and synaptic plasticity [1,2,3]. Normally, IQSEC2 binds to N-methyl-D-aspartate (NMDA)-type glutamate receptors via post-synaptic density protein 95 (PSD-95). Activation of NMDA receptors leads to calcium ion influx, which binds to calmodulin on the IQSEC2 IQ domain. This induces a conformational change, activating the SEC7 catalytic domain, resulting in GTP-GDP exchange on ADP ribosylation factor 6 (ARF6). Activated ARF6 then promotes down-regulation of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors through a c-jun N terminal kinase (JNK)-mediated pathway [1].

Experiments using IQSEC2 transgenic and knockout (KO) mouse models have recapitulated autistic-like behavior and epileptic seizures in affected animals [2]. In IQSEC2 KO mice, the levels of Arf6-GTP remain constitutively high despite the absence of IQSEC2 protein, indicating impaired regulation of the Arf6 guanine nucleotide exchange cycle [2]. Also, studies in these KO mice reveal that IQSEC2 is involved in both inhibitory and stimulatory neurotransmission. Mutated or absent IQSEC2 arrests neuronal development, leading to immature neuronal networks, subsequent aberrant maturation, increased inhibition, and reduced neuronal transmission [2].

In conclusion, IQSEC2 is essential for normal neuronal development and synaptic plasticity through its role in the regulation of glutamate receptor trafficking and neurotransmission. The use of IQSEC2 KO mouse models has been instrumental in understanding its role in conditions such as autism and epilepsy, providing insights into the underlying molecular mechanisms and potential therapeutic targets [1,2].