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 (P)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 with 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 (BA) compared with mice, indicating stronger glutamatergic synapses. Moreover, after fear acquisition mice had a higher number of c-Fos-positive cells than mice in the lateral amygdala (LA), BA, and central amygdala (CE). 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 (PTSD).