Enhanced amygdala inhibitory neurotransmission and its vulnerability to hyperthermic stress in -deficient heterozygous mice.

The sodium pump (Na,K-ATPase, NKA) is a membrane-bound enzyme crucial for maintaining Na/K electrochemical gradients across plasma membranes. NKA constitutes catalytic α and auxiliary β subunits, of which four α and three β isoforms have been identified. The physiological roles of the isoforms are not fully understood; nevertheless, mutations in the human α2 subunit gene have been linked to various neurological disorders, including familial hemiplegic migraine type 2 (FHM2), alternating hemiplegia of childhood (AHC), and epilepsy syndromes, with symptoms typically triggered by physical and psychological stressors. Mice lacking die of respiratory failure at birth, whereas heterozygous fetuses () survive and exhibit increased c-Fos expression in the principal excitatory neurons of the amygdala, suggesting increased neuronal activity. We compared neurotransmission properties in the basolateral amygdala (BLA) between juvenile mice and their wild-type (WT) littermates using acute brain slices to elucidate the physiological significance of α2-NKA. Focal electrical stimulation elicited inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs) in regularly spiking principal neurons within the BLA. Both IPSC and EPSC amplitudes increased linearly with stimulation intensity. IPSCs were consistently larger in than in WT, whereas EPSCs were comparable between the two groups. Notably, the enhanced inhibitory neurotransmission observed in was abolished under hyperthermic stress. The disrupted balance between inhibition and excitation in BLA neuronal networks may be a key pathophysiological mechanism underlying α2-NKA-related disorders. The study findings indicated an enhancement of inhibitory synaptic transmission in the developing amygdala of -deficient heterozygous mice, with hyperthermic stress disrupting this enhanced inhibition. Synaptic imbalances in the amygdala circuit likely contribute to the pathophysiology of neurological disorders associated with NKA α2 subunit dysfunction. These findings enhance our understanding of -related diseases and may introduce novel avenues for exploring the mechanisms by which physical stressors exacerbate these conditions.