Kainate receptor auxiliary subunit NETO2-related cued fear conditioning impairments associate with defects in amygdala development and excitability.

NETO2 is an auxiliary subunit for kainate-type glutamate receptors that mediate normal cued fear expression and extinction. Since the amygdala is critical for these functions, we asked whether mice have compromised amygdala function. We measured the abundance of molecular markers of neuronal maturation and plasticity, parvalbumin positive (PV), perineuronal net positive (PNN), and double positive (PVPNN) cells in the amygdala. We found that adult (but not postnatal day 23) mice had 7.5% reduction in the fraction of PVPNN cells within the total PNN population, and 23.1% reduction in PV staining intensity compared to mice, suggesting that PV interneurons in the adult amygdala remain in an immature state. An immature PV inhibitory network would be predicted to lead to stronger amygdalar excitation. In the amygdala of adult mice, we identified increased glutamatergic and reduced GABAergic transmission using whole-cell patch clamp recordings. This was accompanied by increased spine density of thin dendrites in the basal amygdala compared to mice, indicating stronger glutamatergic synapses. Moreover, after fear acquisition mice had a higher number of c-Fos positive cells than mice in the lateral, basal, and central amygdala. Altogether, our findings indicate that is involved in the maturation of the amygdala PV interneuron network. Our data suggest that this defect, together with other processes influencing amygdala principal neurons, contribute to increased amygdalar excitability, higher fear expression, and delayed extinction in cued fear conditioning, phenotypes that are common in fear-related disorders, including the posttraumatic stress disorder. NETO2 is required for normal fear expression and extinction in cued fear conditioning, but the underlying mechanisms remain unknown. Since amygdala is a central brain region regulating fear responses, we investigated its maturation and function in and mice. mice had stronger fear expression and slower extinction than mice, associated with amygdala hyperexcitability. We propose that defects in the mice involving amygdala PV-interneuron network configuration and amygdala excitation and inhibition imbalance through multiple mechanisms contribute to the fear phenotype of these mice. These findings could inform novel targets for fear-related disorders, such as phobias and posttraumatic stress disorder.