Surface L‐type Ca²⁺ channel expression levels are increased in aged hippocampus

Abstract

Summary Age-related increase in L-type Ca2+ channel (LTCC) expression in hippocampal pyramidal neurons has been hypothesized to underlie the increased Ca2+ influx and subsequent reduced intrinsic neuronal excitability of these neurons that lead to age-related cognitive deficits. Here, using specific antibodies against Cav1.2 and Cav1.3 subunits of LTCCs, we systematically re-examined the expression of these proteins in the hippocampus from young (3–4 month old) and aged (30–32 month old) F344xBN rats. Western blot analysis of the total expression levels revealed significant reductions in both Cav1.2 and Cav1.3 subunits from all three major hippocampal regions of aged rats. Despite the decreases in total expression levels, surface biotinylation experiments revealed significantly higher proportion of expression on the plasma membrane of Cav1.2 in the CA1 and CA3 regions and of Cav1.3 in the CA3 region from aged rats. Furthermore, the surface biotinylation results were supported by immunohistochemical analysis that revealed significant increases of Cav1.2 immunoreactivity in the CA1 and CA3 regions of aged hippocampal pyramidal neurons. In addition, we found a significant increase in the level of phosphorylated Cav1.2 on the plasma membrane in the dentate gyrus of aged rats. Taken together, our present findings provide clear evidence that age-related cognitive deficits cannot be attributed to a global change in L-type channel expression nor to the level of phosphorylation of Cav1.2 on the plasma membrane of hippocampal neurons. Rather increased expression and density of functional LTCCs on the plasma membrane may underlie the age-related increase in L-type Ca2+ channel activity in CA1 pyramidal neurons.

The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions

“…Existing data on age-related changes of LTCC expression are conflicting, ranging from increased LTCC expression in the aged brain [41] to no changes [55] or decreased expression [42,43]. This discrepancy may be partly due to different methods of analysis, since Nunez-Santana and colleagues have recently shown that Cav1.2 and Cav1.3 expression in the hippocampus of 32 months old rat is reduced on the protein, but not on the mRNA level [56]. Further, different age-groups and strains examined in these studies (from 12-month old mice to 32-month old rats) might contribute to the incoherent picture.…”

Hippocampal sharp waves and ripples: Effects of aging and modulation by NMDA receptors and L-type Ca2+ channels

“…Taking into account that the function of NMDARs is altered in the aged hippocampus (Serra et al, 1994, Magnusson et al, 2010 and that clusters are longer in aged we asked what is the involvement of NMDARs in the two age groups Furthermore, in aging hippocampal pyramidal neurons the expression and activity of L-type voltage-dependent calcium channels is enhanced (L-vdcc) (Moyer and Disterhoft, 1994, Kumar et al, 2009b, Nunez-Santana et al, 2013. Given that both NMDARs and L-VDCCs are targets of the aging process and the activity dependent in between them interaction we set out to assess their involvement in the generation SWRs, by using pharmacological blockers independently for NMDARs and L-VDCCs and in combination as well.…”

“…Some important aspects of SWRs including amplitude and patterned occurrence in sequences involve activation of NMDARs (Colgin et al, 2005, Papatheodoropoulos, 2010. In addition, aging is accompanied by alterations in another cellular component involved in learning and memory, the L-type voltage dependent calcium channels (L-vdcc), (Moyer and Disterhoft, 1994, Kumar et al, 2009a, Nunez-Santana et al, 2013.…”

Novel calcium-related targets of insulin in hippocampal neurons

“…Because there is compelling evidence that aspects of cognitive aging may be due to calcium dysregulation that results in enhanced calcium levels (Porter et al , 1997; Thibault et al , 2001; Clodfelter et al , 2002; Hemond & Jaffe, 2005; Gant et al , 2006; Oh et al , 2013) and voltage-gated calcium channels (VGCC) activity (Moyer et al , 1992; Thibault & Landfield, 1996; Thibault et al , 2001; Nunez-Santana et al , 2014), we focused on studying two well-characterized calcium sources in hippocampal neurons. The rationale for this approach was based on recent evidence from our lab that insulin acutely reduces the calcium-dependent afterhyperpolarization (AHP) in neurons recorded from hippocampal slices (Pancani et al , 2013; Maimaiti et al , 2016).…”