Impaired synaptic neurotransmission may underly circuit alterations contributing to behavioral autism spectrum disorder (ASD) phenotypes. A critical component of impairments reported in somatosensory and prefrontal cortex of ASD mouse models are parvalbumin (PV)-expressing fast-spiking interneurons. However, it remains unknown whether PV interneurons mediating hippocampal networks crucial to navigation and memory processing are similarly impaired. Using PV-labeled transgenic mice, a battery of behavioral assays, in vitro patch-clamp electrophysiology, and in vivo 32-channel silicon probe local field potential recordings, we address this question in a Cntnap2-null mutant mouse model representing a human ASD risk factor gene. Cntnap2^-/- mice show a reduction in hippocampal PV interneuron density, reduced inhibitory input to CA1 pyramidal cells, deficits in spatial discrimination ability, and frequency-dependent circuit changes within the hippocampus, including alterations in gamma oscillations, sharp-wave ripples, and theta-gamma modulation. Our findings highlight hippocampal involvement in ASD and implicate interneurons as a potential therapeutical target.

Genetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Local field potential recordings (LFP) were used to screen ∼3300 larvae. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.