Embryonic exposure to valproic acid and neonicotinoid deteriorates the developmental GABA switch and impairs long-term potentiation in the local circuit of intermediate medial mesopallium of chick telencephalon
Embryonic exposure to valproic acid (VPA) and imidacloprid (IMI, a neonicotinoid insecticide) impairs filial imprinting in hatchlings, and the deteriorating effects of VPA are mitigated by post-hatch injection of bumetanide, a blocker of the chloride intruder NKCC1. Here, we report that these exposures depolarized the reversal potential of local GABAergic transmission in the neurons of the intermediate medial mesopallium (IMM), the pallial region critical for imprinting. Furthermore, exposure increased field excitatory post-synaptic potentials in pre-tetanus recordings (fEPSPs) and impaired long-term potentiation by low-frequency tetanic stimulation (LTP). Bath-applied bumetanide rescued the impaired LTP in the VPA 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. However, the transcriptional profiles of IMM slices did not support the expected increase in the NKCC1/KCC2 ratio, suggesting a potential modification of post-transcriptional processes. Instead, exposure to both VPA and IMI downregulated several transcriptional regulators (FOS, NR4A1, and NR4A2) and upregulated the RNA component of signal recognition particles (RN7SL1). As a limited set of response genes were shared, VPA and IMI could cause common neuronal malfunctions via distinct molecular cascades.