Dataset Information

Ca_v1.2 Activity and Downstream Signaling Pathways in the Hippocampus of An Animal Model of Depression.

ABSTRACT: Functional and morphological modifications in the brain caused by major mood disorders involve many brain areas, including the hippocampus, leading to cognitive and mood alterations. Ca_v1.2 channel expression has been found to increase in animals with depressive-like behaviors. Calcium influx through these channels is associated with changes in excitation-transcriptional coupling by several intracellular signal pathways that are regulated by its C-terminus region. However, which of these signaling pathways is activated during the development of depressive-like behaviors is not known. Here, we evaluate the phosphorylation and expression levels of crucial kinases and transcription factors at the hippocampus of rats after 21 days of chronic restraint stress. Our results show that rats subjected to CRS protocol achieve less body weight, have heavier adrenal glands, and exhibit depression-like behaviors such as anhedonia, behavioral despair and decreased social interaction. Ca_v1.2 mRNA and protein expression levels, plus l-type calcium current amplitude, are also increased in treated rats when compared with control animals. Out of the three main signaling pathways activated by l-type currents, we only observed an increment of CaM-NFAT axis activity with the concomitant increment in Fas ligand expression. Thus, our results suggest that CRS activates specific pathways, and the increased expression of Ca_v1.2 could lead to neuronal death in the hippocampus.

SUBMITTER: Moreno C

PROVIDER: S-EPMC7762021 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Ca<sub>v</sub>1.2 Activity and Downstream Signaling Pathways in the Hippocampus of An Animal Model of Depression.

Moreno Cristian C Hermosilla Tamara T Hardy Paulina P Aballai Víctor V Rojas Patricio P Varela Diego D

Cells 20201204 12

Functional and morphological modifications in the brain caused by major mood disorders involve many brain areas, including the hippocampus, leading to cognitive and mood alterations. Ca<sub>v</sub>1.2 channel expression has been found to increase in animals with depressive-like behaviors. Calcium influx through these channels is associated with changes in excitation-transcriptional coupling by several intracellular signal pathways that are regulated by its C-terminus region. However, which of th ...[more]

PMID: 33291797

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Project description:Voltage-gated Cav1.2 and Cav1.3 (L-type) Ca2+ channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca2+-dependent facilitation of voltage-gated Cav1.3 Ca2+ channels in transfected cells. Mice lacking densin (densin KO) exhibit defects in synaptic plasticity, spatial memory, and increased anxiety-related behaviors-phenotypes that more closely match those in mice lacking Cav1.2 than Cav1.3. Therefore, we investigated the functional impact of densin on Cav1.2. We report that densin is an essential regulator of Cav1.2 in neurons, but has distinct modulatory effects compared with its regulation of Cav1.3. Densin binds to the N-terminal domain of Cav1.2, but not that of Cav1.3, and increases Cav1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Cav1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Cav1.2 channels, overexpression of densin increases the clustering of Cav1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Cav1.2 in the brain, as well as Cav1.2 current density and signaling to the nucleus, are reduced in neurons from densin KO mice. We conclude that densin is an essential regulator of neuronal Cav1 channels and ensures efficient Cav1.2 Ca2+ signaling at excitatory synapses.SIGNIFICANCE STATEMENT The number and localization of voltage-gated Cav Ca2+ channels are crucial determinants of neuronal excitability and synaptic transmission. We report that the protein densin-180 is highly enriched at excitatory synapses in the brain and enhances the cell surface trafficking and postsynaptic localization of Cav1.2 L-type Ca2+ channels in neurons. This interaction promotes coupling of Cav1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Cav1.2 in regulating cognition and mood.

Dataset Information

Ca_v1.2 Activity and Downstream Signaling Pathways in the Hippocampus of An Animal Model of Depression.

Publications

Ca<sub>v</sub>1.2 Activity and Downstream Signaling Pathways in the Hippocampus of An Animal Model of Depression.

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Dataset Information

Cav1.2 Activity and Downstream Signaling Pathways in the Hippocampus of An Animal Model of Depression.

Publications

Ca<sub>v</sub>1.2 Activity and Downstream Signaling Pathways in the Hippocampus of An Animal Model of Depression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Ca_v1.2 Activity and Downstream Signaling Pathways in the Hippocampus of An Animal Model of Depression.