Estradiol Reverses a Calcium-Related Biomarker of Brain Aging in Female Rats

Abstract

An increase in L-type voltage-gated calcium channel (LTCC) current is a prominent biomarker of brain aging and is believed to contribute to cognitive decline and vulnerability to neuropathologies. Studies examining age-related changes in LTCCs have focused primarily on males, although estrogen (17␤-estradiol, E2) affects calcium-dependent activities associated with cognition. Therefore, to better understand brain aging in females, the effects of chronic E2 replacement on LTCC current activity in hippocampal neurons of young and aged ovariectomized rats were determined. The zipper slice preparation was used to expose cornu ammonis 1 (CA1) pyramidal neurons for recording LTCC currents using the cell-attached patch-clamp technique. We found that an age-related increase in LTCC current in neurons from control animals was prevented by E2 treatment. In addition, in situ hybridization revealed that within stratum pyramidale of the CA1 area, mRNA expression of the Ca v 1.2 LTCC subunit, but not the Ca v 1.3 subunit, was decreased in aged E2-treated rats. Thus, the reported benefits of E2 on cognition and neuronal health may be attributed, at least in part, to its age-related decrease in LTCC current.

Calcium's role as nuanced modulator of cellular physiology in the brain

“…Nevertheless, the genomic mechanism appears to reduce L-VGCC activity but the rapid mechanism increases L-VGCC activity. This suggests the possibility that L-VGCC channel expression and calcium influx are dynamically regulated by estradiol, and as we and others have previously shown, can be altered in aging [66; 71]. …”

“…Another hormone, estradiol, has also been shown to modulate L-VGCC expression and activity in hippocampal neurons and in GnRH related cells [66; 67]. Interestingly, in both of these cell types estradiol decreased Ca v 1.3 expression but not Ca v 1.2.…”

Reduction in neuronal L-type calcium channel activity in a double knock-in mouse model of Alzheimer's disease

“…Preparation of partially dissociated “zipper” slices from mice was carried out as described by earlier studies on adult guinea pigs [10] and aged rats [8, 11, 12]. Mice were decapitated after CO 2 asphyxiation, and brains placed briefly in ice-cold oxygenated (95%O2/5%CO2) artificial cerebral spinal fluid (ACSF) containing (in mM): 114 NaCl, 2.5 KCl, 2 MgCl 2 , 30 NaHCO 3 , 10 Glucose, and 0.1 CaCl 2 (pH 7.4).…”

FK506-binding protein 1b/12.6: A key to aging-related hippocampal Ca2+ dysregulation?

“…The sAHP is generated by Ca 2+ influx via voltage-gated Ca 2+ channels (VGCCs) that activates hyperpolarizing K + currents, which in turn dampen postsynaptic excitability. In addition to the larger sAHP, multiple other Ca 2+ -related electrophysiological processes have since been shown to be increased in hippocampal pyramidal neurons of aged animals, including Ca 2+ action potential duration, L-type VGCC (L-VGCC) activity, voltage-activated Ca 2+ transients, long-term depression and action potential accommodation (Brewer et al, 2009; Disterhoft et al, 1996; Foster and Norris, 1997; Moyer et al, 1992; Pitler and Landfield, 1990; Potier et al, 1993; Thibault et al, 2001; Thibault and Landfield, 1996). Importantly, several of these enhanced Ca 2+ -related functions are correlated with impairment of learning or synaptic plasticity (Disterhoft and Oh, 2007; Disterhoft et al, 1996; Kumar and Foster, 2004; Thibault et al, 2001; Thibault and Landfield, 1996; Tombaugh et al, 2005).…”

“…One possibility is that a decrease in the biosynthesis of energy-expensive proteins, notably including FKBPs, might result from a metabolic shift that appears to develop in neurons and glia of the hippocampus during aging of females (Brinton, 2008; Yau and Seckl, 2012) and males (Kadish et al, 2009; Rowe et al, 2007). These metabolic alterations in turn may depend on age-related variations in endocrine status, as some hormones (e.g., estrogens and progestins) appear to interact strongly with brain aging and brain metabolism (Brewer et al, 2009; Foster, 2012; Simpkins and Singh, 2008; Sohrabji and Bake, 2006; Xin et al, 2002). Additionally, adrenal stress hormones (glucocorticoids) exert major effects on metabolism and have long been linked to brain aging (Porter and Landfield, 1998).…”