Gene's Role May Inform Treatment for Neuropsychiatric Diseases

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Conditional deletion of the Cav1.2 gene in the forebrain causes deficits in hippocampal neurogenesis.
Conditional deletion of the Cav1.2 gene in the forebrain causes deficits in hippocampal neurogenesis.

New research findings published in eNeuro indicate that a gene associated with many major neuropsychiatric diseases plays a key role in the survival of young hippocampal neurons, which may have implications for future treatment approaches.1

In a previous study, a gene called CACNA1C was one of two genes associated with increased risk for major depression, schizophrenia, bipolar disorder, autism, and attention deficit hyperactivity disorder (ADHD), though the underlying mechanisms have been unclear.2 When the gene is inactivated in the forebrain, mice show significantly elevated anxiety-like behavior. Importantly, anxiety is a major feature of the 5 diseases in which the gene is implicated.


CACNA1C encodes the voltage-gated L-type calcium channel (LTCC) Cav1.2, which allows cellular influx of calcium following transient changes in membrane potential,” wrote the authors of the current study, representing multiple US universities, including Cornell University in New York and the University of Iowa as well as Technical University Munich in Germany. “This ultimately activates downstream pathways of genetic transcription,” including the proneurogenic molecule brain-derived neurotrophic factor (BDNF), they said. It's known that Cav1.2 is important for synaptic plasticity involved in neuropsychiatric illness, drug addiction, and processes related to reward, fear, and cognition. Unlike Cav1.3, which is the other brain-specific LTCC, Cav1.2 also mediates anxiety-like behavior in mice.

According to the authors of the new study, previous findings indicate that Cav1.3 modulates “both proliferation of postnatal neural precursor cells (NPCs) and survival of young hippocampal neurons in the hippocampus, such that elimination of Cav1.3 results in reduced size of the dentate gyrus,” although “it has not previously been determined whether Cav1.2 exerts a unique or complementary role in LTCC-mediated hippocampal neurogenesis.” The researchers explored this further because postnatal hippocampal neurogenesis plays a role in all 5 neuropsychiatric conditions that were previously linked with variations in CACNA1C. They investigated the degree of “hippocampal neurogenesis and other neurophysiologic parameters following spatial and temporal manipulation of Cav1.2 expression,” they explained.

According to results, conditional genetic deletion of the Cav1.2 in the forebrain causes deficits in postnatal hippocampal neurogenesis due to increased death of young hippocampal neurons and results in diminished BDNF expression. No change was observed in NPC proliferation, hippocampal size, or dentate gyrus thickness, indicating differential roles of Cav1.2 and Cav1.3 in regulating survival of young hippocampal neurons.

In addition, the researchers didn't observe differences in either basal or stress-induced corticosterone levels between wild-type and knockout mice. This indicates that the diminished neurogenesis is not a result of genotype-dependent differences in corticosterone, which, at high levels, is known to reduce hippocampal neurogenesis.

Postnatal hippocampal neurogenesis was restored when the mice were treated with a neuroprotective compound called P7C3-A20. The BDNF deficit was not affected, however, which could indicate that “P7C3 compounds offer an alternative therapeutic route to restore neurogenesis in a manner that circumvents deficient BDNF signaling through an independent mechanism,” the authors stated. These findings regarding “the role of Cav1.2 in young hippocampal neurons survival may provide new approaches for understanding and treating neuropsychiatric disease associated with aberrations in CACNA1C,” and medications derived from the P7C3 class of neuroprotective compounds could eventually offer new treatment options, they concluded.

References

1. Lee AS, De Jesús-Cortés H, Kabir ZD, et al. The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons. eNeuro. 2016; 3(2).  

2. Cross-Disorder Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013; 45(9):984-94.


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