The absence of the calcium‐buffering protein calbindin is associated with faster age‐related decline in hippocampal metabolism

Abstract

Although reductions in the expression of the calcium-buffering proteins calbindin D-28K (CB) and parvalbumin (PV) have been observed in the aging brain, it is unknown whether these changes contribute to age-related hippocampal dysfunction. To address this issue, we measured basal hippocampal metabolism and hippocampal structure across the lifespan of C57BL/6J, calbindin D-28k knockout (CBKO) and parvalbumin knockout (PVKO) mice. Basal metabolism was estimated using steady state relative cerebral blood volume (rCBV), which is a variant of fMRI that provides the highest spatial resolution, optimal for the analysis of individual subregions of the hippocampal formation. We found that like primates, normal aging in C57BL/6J mice is characterized by an age-dependent decline in rCBV-estimated dentate gyrus metabolism. Although abnormal hippocampal fMRI signals were observed in CBKO and PVKO mice, only CBKO mice showed accelerated age-dependent decline of rCBV-estimated metabolism in the dentate gyrus. We also found age-independent structural changes in CBKO mice, which included an enlarged hippocampus and neocortex as well as global brain hypertrophy. These metabolic and structural changes in CBKO mice correlated with a deficit in hippocampus-dependent learning in the active place avoidance task. Our results suggest that the decrease in CB that occurs during normal aging is involved in age-related hippocampal metabolic decline. Our findings also illustrate the value of using multiple MRI techniques in transgenic mice to investigate mechanisms involved in the functional and structural changes that occur during aging.

The calcium-binding protein parvalbumin modulates the firing 1 properties of the reticular thalamic nucleus bursting neurons

“…6, A and B) and Ca v 3.3 (Fig. 6, C and D), which are specifically expressed in the rodent RTN (Talley et al 1999) and display different activation and inactivation kinetics (Gomora et al 2002;Park et al 2004) associated with the generation of the bursts of spikes. The somatic expression of Ca v 3.2 in WTs (n ϭ 12 sections from 3 mice, 10 ROIs/section) and PVKOs (n ϭ 12 sections from 4 mice, 10 ROIs/section) was on average equal to 67 Ϯ 3 (means Ϯ SE) and 92 Ϯ 4 pixels/m 2 , respectively.…”

Visual thalamocortical circuits in parvalbumin-deficient mice

“…PV-deficient (PVKO) mice were originally generated on a mixed C57Bl/6J Â 129/OlaHsd genetic background (Schwaller et al, 1999) and backcrossed to C57Bl/6J for 10 generations and are thus considered to be congenic to C57Bl/6J (Moreno et al, 2011) …”

The effect of parvalbumin deficiency on the acoustic startle response and prepulse inhibition in mice

“…Parvalbumin-deficient mice (PV−/−) were generated by homologous recombination [23] and backcrossed to C57BL/6 mice for >10 generations and are considered to be congenic to C57Bl/6 mice [18]. PV−/− mice (n = 9, mean body weight 29.0 ± 1.6 g) obtained directly from the animal facility of the University of Fribourg were genotyped by PCR [23] to validate the inactivation of the Pvalb gene.…”

“…For PV, this is the case in fast-twitch muscles [23] and in a specific subpopulation of neurons [2], where PV is implicated in the subtle regulation and timing of Ca 2+ signals preand postsynaptically. In the brain, PV is almost exclusively present in subpopulations of inhibitory GABAergic interneurons in different brain regions including the neocortex, cerebellum, hippocampus and the reticular nucleus of the thalamus [2][3][4]18]. In the auditory system PV is expressed in cochlear hair cells [11] and in globular bushy cells' endings in the large calyx of Held on the principal cells in the medial nucleus of the trapezoid body [8].…”