Absence of the calcium-binding protein calretinin, not of calbindin D-28k, causes a permanent impairment of murine adult hippocampal neurogenesis

Abstract

Calretinin (CR) and calbindin D-28k (CB) are cytosolic EF-hand Ca2+-binding proteins and function as Ca2+ buffers affecting the spatiotemporal aspects of Ca2+ transients and possibly also as Ca2+ sensors modulating signaling cascades. In the adult hippocampal circuitry, CR and CB are expressed in specific principal neurons and subsets of interneurons. In addition, CR is transiently expressed within the neurogenic dentate gyrus (DG) niche. CR and CB expression during adult neurogenesis mark critical transition stages, onset of differentiation for CR, and the switch to adult-like connectivity for CB. Absence of either protein during these stages in null-mutant mice may have functional consequences and contribute to some aspects of the identified phenotypes. We report the impact of CR- and CB-deficiency on the proliferation and differentiation of progenitor cells within the subgranular zone (SGZ) neurogenic niche of the DG. Effects were evaluated (1) two and four weeks postnatally, during the transition period of the proliferative matrix to the adult state, and (2) in adult animals (3 months) to trace possible permanent changes in adult neurogenesis. The absence of CB from differentiated DG granule cells has no retrograde effect on the proliferative activity of progenitor cells, nor affects survival or migration/differentiation of newborn neurons in the adult DG including the SGZ. On the contrary, lack of CR from immature early postmitotic granule cells causes an early loss in proliferative capacity of the SGZ that is maintained into adult age, when it has a further impact on the migration/survival of newborn granule cells. The transient CR expression at the onset of adult neurogenesis differentiation may thus have two functions: (1) to serve as a self-maintenance signal for the pool of cells at the same stage of neurogenesis contributing to their survival/differentiation, and (2) it may contribute to retrograde signaling required for maintenance of the progenitor pool.

The effect of electroconvulsive seizure on survival, neuronal differentiation, and expression of the maturation marker in the adult mouse hippocampus

“…The role of CR in immature neurons has been proposed, and CR knockout mice show reduced survival and migration of newborn neurons in the DG (Todkar et al . ). Therefore, it is hypothesized that elevated CR expression in immature neurons may selectively contribute to the survival effect of ECS.…”

“…The increase in CR(+) cells in the DG has also been reported for other stimuli that increase neurogenesis, such as enriched environments, running, and kainate‐induced seizures (Todkar et al . ). It should be noted that Brandt et al .…”

“…CR is a Ca 2+ binding protein and functions as a Ca 2+ buffer, affecting Ca 2+ signaling cascades in neurons (Camp and Wijesinghe 2009). The role of CR in immature neurons has been proposed, and CR knockout mice show reduced survival and migration of newborn neurons in the DG (Todkar et al 2012). Therefore, it is hypothesized that elevated CR expression in immature neurons may selectively contribute to the survival effect of ECS.…”

Melatonin maintains calcium-binding calretinin-positive neurons in the dentate gyrus during aging of Balb/C mice

“…Previous work showed that chronic treatment with melatonin increased the number of CR-neurons in the DG of young C57Bl6 mice (Ramirez-Rodriguez et al, 2009). Calretinin is a Ca ++ -binding protein (Kuznicki et al, 1996;Schwaller, 2014) that is essential for neuronal development in the DG during adulthood (Brandt et al, 2003;Todkar et al, 2012). In this sense, it has been proposed that in maturing granule cells, CR could function as a Ca ++ -sensor during Ca ++ transients occurring with the onset of synaptic activity and also linked to the GABA-dependent depolarizing currents (Ge et al, 2006).…”

“…This protein acts as a calcium-buffer/binding (Schwaller, 2014) and is essential for murine hippocampal neurogenesis (Brandt et al, 2003;Todkar et al, 2012). During aging CR-protein expression and the number of CR-neurons decrease in the whole hippocampus (Bu et al, 2003;Lee et al, 2010;Mirochnic et al, 2009).…”