Degeneration of the Amygdala/Piriform Cortex and Enhanced Fear/Anxiety Behaviors in Sodium Pump α2 Subunit (Atp1a2)-Deficient Mice

Abstract

The sodium pump is the enzyme responsible for the maintenance of Na+ and K+ gradients across the cell membrane. Four isoforms of the catalytic alpha subunit have been identified, but their individual roles remain essentially unknown. To investigate the necessary functions of the alpha2 subunit in vivo, we generated and analyzed mice defective in the alpha2 subunit gene. Mice homozygous for the alpha2 mutation died just after birth and displayed selective neuronal apoptosis in the amygdala and piriform cortex. In these regions, high expression of c-Fos before apoptosis indicated neural hyperactivity, and re-uptake of glutamic acid and GABA into P2 fraction containing crude synaptosome was impaired. These results indicate that the alpha2 subunit plays a critical role regulating neural activity in the developing amygdala and piriform cortex. Further supporting a role of the alpha2 subunit in the function of the amygdala, heterozygous adult mice showed augmented fear/anxiety behaviors and enhanced neuronal activity in the amygdala and piriform cortex after conditioned fear stimuli.

Mutation I810N in the α3 isoform of Na + ,K + -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

“…Although the ␣2-isoform of Na ϩ ,K ϩ -ATPase present in glial cells has been promoted as the major isoform involved in K ϩ clearance, there are indications that neuronal Na ϩ ,K ϩ -ATPase could be more important than glial Na ϩ ,K ϩ -ATPase for K ϩ clearance after epileptiform activity induced in hippocampal slices (8). Our finding that ␣3 is the functionally dominant ␣ subunit in the adult brain is consistent with the reported lack of seizures in ␣1 or ␣2 heterozygous mice (21,24). Reduced ␣3-mediated Na ϩ transport in neurons might furthermore lead to a greater elevation in posttetanic intracellular Na ϩ with a concomitant reduction in Na ϩ /Ca 2ϩ exchanger-mediated calcium extrusion, and dysregulated calcium transients could lead to a rise of the intracellular Ca 2ϩ level with accumulation of glutamate in the synaptic cleft (6) and to over-activation of calcineurin and internalization of GABA receptors (25,26).…”

Deficiency in Na,K-ATPase α Isoform Genes Alters Spatial Learning, Motor Activity, and Anxiety in Mice

“…No significant differences in the number of head dips were observed among the genotypes (Fig. 2C) Ikeda et al (2003) reported increased expression of c-Fos in the piriform cortex and amygdala in homozygous null ␣2 mutants on E17.5-E18.5 and increased expression in adult heterozygous mutants after conditioned fear compared with no differences in expression in heterozygotes kept in their home cage. To determine whether a 5 min forced swim would also produce differences in c-Fos in ␣2 heterozygotes, we examined c-Fos expression in ␣2 ϩ/Ϫ mice as adults by immunohistochemistry.…”

“…Two general behavioral areas were examined, anxiety and learning. Anxiety and motor activity were assessed in an elevated zero maze and an automated open field based on data that ␣2 heterozygous mice exhibit increased anxiety on these tests and show increased c-Fos expression in the amygdala and piriform cortex after conditioned fear (Ikeda et al, 2003). Furthermore, because dopamine and serotonin uptake are affected by Na,K-ATPase inhibition and these neurotransmitters directly modulate motor activity, locomotor activity after methamphetamine-induced stimulation was used as a means to unmask monoamine dysfunction in the heterozygous mice to determine whether individual Na,K-ATPase isoforms contribute to dopamine or serotonin signaling (Steffens and Feuerstein, 2004).…”

Familial Hemiplegic Migraine

“…[76][77][78] Impaired clearance of neurotransmitters and enhanced neuronal excitation in the amygdala and pyriform cortex were shown in Atp1a2 Ϫ/Ϫ mice at the embryonic stage. 79 These mice die at birth because of lack of spontaneous respiratory activity due to functional impairment of the brainstem respiratory neurons, probably as a result of elevated intracellular [Cl Ϫ ] that would switch the GABA response from hyperpolarization to depolarization; the data suggest a specific coupling between the ␣ 2 Na ϩ ,K ϩ -ATPase and the neuron-specific K ϩ -Cl Ϫ cotransporter, which excludes Cl Ϫ ions from the cytosol in respiratory center neurons. 80 A specific colocalization of the ␣ 2 isoform of the Na ϩ ,K ϩ pump with the Na ϩ /Ca 2ϩ exchanger in microdomains that overlie subplasmalemmal endoplasmic reticulum was demonstrated in cultured astrocytes, suggesting a specific functional role of this isoform also in the regulation of intracellular Ca 2ϩ , particularly in the endoplasmic reticulum.…”