Abstract
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 Neto2-/- 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 (PV+PNN+) cells in the Neto2-/- amygdala. We found that Neto2-/- adult (but not postnatal day 23) mice had 7.5% reduction in the fraction of PV+PNN+ cells within the total PNN+ population, and 23.1% reduction in PV staining intensity compared to Neto2+/+ mice, suggesting that PV interneurons in the adult Neto2-/- 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 Neto2-/- 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 Neto2+/+ mice, indicating stronger glutamatergic synapses. Moreover, after fear acquisition Neto2-/- mice had a higher number of c-Fos positive cells than Neto2+/+ mice in the lateral, basal, and central amygdala. Altogether, our findings indicate that Neto2 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.
Significance statement 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 Neto2-/- and Neto2+/+ mice. Neto2-/- mice had stronger fear expression and slower extinction than Neto2+/+ mice, associated with amygdala hyperexcitability. We propose that defects in the Neto2-/- 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.
Footnotes
A. Authors report no conflict of interest
Jane and Aatos Erkko Foundation (to IH, SL and VV), Sigrid Jusélius Foundation (to IH and EC), Academy of Finland (to EC), Oskar Öflund Foundation (to MM), Finnish Cultural Foundation (to MM), Jalmari and Rauha Ahokas Foundation (to MM), A*MIDEX grant (n° ANR-11-IDEX-0001-02) funded by the French Government «Investissements d’Avenir» program (to AG).
Marie Mennesson and Ester Orav Equal contribution.
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