Suppressed Calbindin Levels in Hippocampal Excitatory Neurons Mediate Stress-Induced Memory Loss

Abstract

Calbindin modulates intracellular Ca dynamics and synaptic plasticity. Reduction of hippocampal calbindin levels has been implicated in early-life stress-related cognitive disorders, but it remains unclear how calbindin in distinct populations of hippocampal neurons contributes to stress-induced memory loss. Here we report that early-life stress suppressed calbindin levels in CA1 and dentate gyrus (DG) neurons, and calbindin knockdown in adult CA1 or DG excitatory neurons mimicked early-life stress-induced memory loss. In contrast, calbindin knockdown in CA1 interneurons preserved long-term memory even after an acute stress challenge. These results indicate that the dysregulation of calbindin in hippocampal excitatory, but not inhibitory, neurons conveys susceptibility to stress-induced memory deficits. Moreover, calbindin levels were downregulated by early-life stress through the corticotropin-releasing hormone receptor 1-nectin3 pathway, which in turn reduced inositol monophosphatase levels. Our findings highlight calbindin as a molecular target of early-life stress and an essential substrate for memory.

Prefrontal Nectin3 Reduction Mediates Adolescent Stress-Induced Deficits of Social Memory, Spatial Working Memory, and Dendritic Structure in Mice

“…Our previous studies have linked hippocampal nectin3 to early-life stress-induced spine loss and cognitive deficits [16,48]. As the first study to examine nectin3 in the PFC, we first confirmed that nectin3 is expressed in both excitatory and inhibitory neurons in mouse mPFC, similar to our findings in the hippocampus [30]. How nectin3 contributes to the stress effects on the neurodevelopment of the adolescent PFC is unknown.…”

“…All of the behavioral tests were carried out between 09:00 and 16:00 as described previously [28,30,31]. Behavior in the open field was analyzed using ANY-maze 4.98 (Stoelting, Wood Dale, IL).…”

Social subordination induced by early life adversity rewires inhibitory control of the prefrontal cortex via enhanced Npy1r signaling

“…3g-i). These results are in line with recent findings suggesting alterations in inhibitory neuron networks that occur as a consequence of ELS [24,25]. In order to assess if these morphological and functional differences stemmed from persistent increases in corticosterone levels or if ELS mice were hyperreactive to stressful insults, we determined the concentration of corticosterone under basal conditions (between days of experimentation) and immediately following tube test encounters ( Supplementary Fig.…”

Posterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect

“…We speculate that anxiolytic and anxiogenic information from pBLA and aBLA may be respectively integrated in vCA1 and/or may be further transmitted to distinct downstreams of vCA1 Calb1+ and vCA1 Calb1− neurons, by which they control whether and where to go or not to go when facing a complicated environment. Given that the excitatory neurons in the aBLA and pBLA could be telegraphed through mutual inhibition 19 and that Calb1+ neurons consist of excitatory neurons and GABAergic interneurons 31 , it will be interesting in future studies to determine whether aBLA-vCA1 and pBLA-vCA1 circuits influence each other and how their coordination ultimately occurs in a conflict environment. In addition, the BLA shares reciprocal projections with the vCA1 32,33 , and the vCA1-BLA circuit encodes contextual information in fear 33 .…”