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    • In perimenstrual catamenial epilepsy there is emerging evide

    2021-11-23

    In perimenstrual catamenial epilepsy, there is emerging evidence to suggest that P withdrawal plays a key role in seizure exacerbations occurring around the time of menstruation (Backstrom et al., 1984, Bonuccelli et al., 1989, Scharfman and MacLusky, 2006). The mechanisms underlying ovarian cycle-related α2-subunit plasticity remain unclear. However, there is evidence that cyclical fluctuations in steroid hormones across the estrous cycle regulate several GABA-A receptor subunits at the diestrus phase (Maguire et al., 2005, Gangisetty and Reddy, 2010, Reddy et al., 2012, Wu et al., 2013, Carver et al., 2014). Previous studies reported increased α4 and δ-subunits at diestrus relative to estrus phase (Maguire et al., 2005, Wu et al., 2013). Other studies demonstrated upregulation of α4 and δ-subunits in response to P treatment and neurosteroid withdrawal (Reddy and Kulkarni, 1999, Mostallino et al., 2006, Gangisetty and Reddy, 2010, Wu et al., 2013, Carver et al., 2014). Similarly, there is evidence for changes in GABA-A receptor subunit plasticity on proestrus when α4 and δ-subunit expression increases significantly in hippocampus CA1 (Sabaliauskas et al., 2014). Moreover, P-induced increases in α4 and δ-subunit are increased by the addition of estradiol, which is elevated on proestrus (Shen et al., 2005). A number of studies shown that the α2-subunit is linked to behavior conditions such as anxiety and depression (Low et al., 2000, Vollenweider et al., 2011). Altered expression of α1 and α2-subunits in different estrous cycle stages have been reported previously (Byrnes et al., 2007). There are some discrepancies in expression of these subunits during estrous cycle stages. It is possible that these discrepancies occurred due to species variation, selected SAR405 region, and technique used. The overall significance of changes in the α2 and other subunits during the estrous cycle need to be reconciled for physiological significance. Aside from α2, there are other synaptic subunits, such as γ2, that are also regulated during the estrous cycle. For example, there was significant reduction in γ2 expression at the diestrous phase (Maguire et al., 2005). In accordance with the suggested rules of GABA-A receptor subunit assembly, γ2-containing receptors are expressed at synaptic sites. Moreover, the loss of one subunit can result in compensatory upregulation of partner subunits. Therefore, it is likely that the alterations in α2-subunit during the estrous cycle are reflected by changes in partnering subunits. The net contribution of these changes are consistent with functional alterations in GABAergic currents (Maguire et al., 2005, Wu et al., 2013). The present study utilizes endogenous fluctuations in P and neurosteroids across the estrous cycle to examine expressional plasticity of the α2-subunit in the hippocampal subfields. We used highly sensitive, optimized assays for subunit mRNA expression (Gangisetty and Reddy, 2009). We found regulation of α2-subunit expression to be subfield-specific, with greater α2-subunit expression in the CA3 and DG during the diestrus compared to estrus phase (Fig. 1). Emerging evidence suggests that the α2-subunit is involved in synaptic targeting, but pentameric channels made of α2β3δ receptors have very low affinity to GABA (Wu et al., 2012). Receptors with α2 and δ-subunit are abundantly present in the molecular layer of the DG in the rat brain (Sperk et al., 1997). Therefore, it is still not clear whether α2-containing receptors assemble extrasynaptically with the δ-subunit or respond to low micromolar extracellular GABA to regulate tonic inhibition. Nevertheless, substantial increases in synaptic α2 levels could affect overall neuronal excitability. For example, the α2βγ2 receptor has faster activation kinetics, prolonged open duration and bursting activity, and slower deactivation/decay time than α1βγ2 (Lavoie et al., 1997). A large switch from α1 to α2-containing receptors in the hypothalamus has been previously shown to be coupled with slower phasic current decay (Brussaard et al., 1997, Brussaard and Herbison, 2000). Therefore, a relative increase in α2-subunit proportion could result in greater net inhibitory current in neuronal networks. Durkin et al. (2011) have created a glutamine to methionine knock-in mouse line in which the neurosteroid potentiation site on the α2-subunit has been disrupted. This mutation reduced the effect of neurosteroids on the decays of phasic currents. Homozygous mice displayed a tendency toward increased anxiety-like behavior, suggesting a role for α2-receptor in anxiety behavior.