Zebrafish model for IQSEC2-depenednt neurodevelopmental disorders

Intellectual disability (ID) is a neurodevelopmental disorder characterized by impaired cognitive functioning coupled with a deficit in adaptive behavior. A severe X-linked ID is caused by mutations in the IQSEC2 gene, frequently accompanied by epilepsy and autism. IQSEC2 is localized at the postsynaptic density (PSD) of excitatory synapses where it forms a protein complex with N-methyl-D-aspartate-type (NMDA) glutamate receptors and regulates surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Its IQ domain binds calmodulin, and its SEC7 domain exchanges GTP for GDP on ARF6. Studies suggest that IQSEC2 has a key role in regulating synaptic plasticity, neuron morphology and development. Iqsec2 knockout (KO) mice show increased activation of GEF resulting in elevated production of the active form of Arf6. These mice also demonstrate hyperactivity, altered anxiety responses, decreased social interactions, delayed learning capacity, and severe seizures. However, the localization and the functional role of IQSEC2 at the cellular levels are unclear. We used CRISPR to generate an iqsec2 mutant (iqsec2-/-) zebrafish. The zebrafish is a transparent vertebrate with conserved genome sequence and brain function. Whole mount in situ hybridization (ISH) studies showed that iqsec2 is primarily expressed in the hypothalamus and the forebrain of larvae, and is widely expressed in the adult brain. Imaging of fluorescent synapses in live larvae showed reduced synaptic density in specific brain regions. High throughput behavioral analysis showed that iqsec2-/- larvae are hyperactive. Future work in this fish model are expected to reveal the cellular mechanism of IQSEC2-deficincy, and may help to uncover effective treatments for ID, epilepsy and autism.