Embryonic exposure to valproic acid and neonicotinoid deteriorates the hyperpolarizing GABA shift and impairs long-term potentiation of excitatory transmission in the local circuit of intermediate medial mesopallium of chick telencephalon.

Abstract

Embryonic exposure to valproic acid and imidacloprid (a neonicotinoid insecticide) impairs filial imprinting in hatchlings, and the deteriorating effects of valproic acid are mitigated by post-hatch injection of bumetanide, a blocker of the chloride intruder Na-K-2Cl cotransporter 1. Here, we report that these exposures depolarized the reversal potential of local GABAergic transmission in the neurons of the intermediate medial mesopallium, the pallial region critical for imprinting. Furthermore, exposure increased field excitatory post-synaptic potentials in pre-tetanus recordings and impaired long-term potentiation (LTP) by low-frequency tetanic stimulation. Bath-applied bumetanide rescued the impaired LTP in the valproic acid slices, whereas VU0463271, a blocker of the chloride extruder KCC2, suppressed LTP in the control slices, suggesting that hyperpolarizing GABA action is necessary for the potentiation of excitatory synaptic transmission. Whereas a steep increase in the gene expression of KCC2 appeared compared to NKCC1 during the peri-hatch development, significant differences were not found between valproic acid and control post-hatch chicks in these genes. Instead, both valproic acid and imidacloprid downregulated several transcriptional regulators (FOS, NR4A1, and NR4A2) and upregulated the RNA component of signal recognition particles (RN7SL1). Despite different chemical actions, valproic acid and imidacloprid could cause common neuronal effects that lead to impaired imprinting.