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Using the Beck Depression Inventory, the researchers analyzed the effects of all the CACNA1C variants and adult trauma on current depression symptom.

32 out of 465 tested SNPs in the CACNA1C locus demonstrated significant interactions with adult trauma exposure. After correction for multiple testing, of the 32, two of them remained significant

In both cases individuals carrying at least one minor allele and without trauma history displayed higher Beck Depression Inventory scores in comparison to the major allele group.

The opposite was observed for minor allele carriers with the highest degree of lifetime trauma exposure.

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The results for Embryonic mice will be displayed in the following four sections:
(I) Dark/Light Box Test
(II) Forced Swim Test (FST)

(III) Water Cross-Maze (WCM)
(IV) Sociability test

(V) The Relation Between CACNA1C Deletion And CSDS

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Cav1.2-DevGlu-CKO mice showed increased anxiety in the dark–light box test

In general mice tend to avoid the lit zone due to anxiety.
Here,  we see lower time spent in the lit zone and a lower number of entries into the lit zone by knockout mice, suggesting enhanced anxiety.

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Saw increased active stress-coping behavior. Mouse’s struggling increased.
KO mice also displayed increased active stress-coping, evident by decreased immobility. This signifies that mice spent more time struggling and were more anxious compared to controls.

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Schizophrenia, bipolar disorder and major depressive disorder are moderately to highly heritable psychiatric disorders (Cardno and Owen, 2014).

Schizophrenia is characterized by delusions and hallucinations which come with a loss of reality. There are also cognitive impairments with patients that have schizophrenia.

Bipolar disorder is characterized by recurrent episodes of mania and depression and states that fall in between (Geddes, 2003) .

Depression is characterized by a persistence in low mood for long periods of time (Bora & Berk, 2016) .

Even though these three disorders have different and varying symptoms they are however genetically linked based on past GWAS studies (Green et al, 2009, Ripke et al, 2011, Smollar 2013). These GWAS studies have revealed that these psychiatric disorders have been associated with SNPs in the CACNA1C gene that codes for the α1 subunit of Cav 1.2 , an L-type voltage gated calcium channel (Cardno and Owen, 2014).

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CACNA1C, codes for the pore-forming α1C subunit of the L-type voltage-gated calcium channel (LTCC) referred to as Cav 1.2 (Bhat et al., 2012).

Cav 1.2 plays an important role in dendritic development, neuronal survival, synaptic plasticity, memory formation, learning and behaviour through transcriptional regulation (Bhat et al., 2012).

Previous research on CACNA1C expression during development and adulthood can result in diverging behavioural outcomes and differentially impact cognition, sociability which indicates an environmental factor (Dedic et al., 2018).

Increased research of CACNA1C expression can spawn pharmacological manipulation of Cav1.2 in hopes of alleviating symptoms of related psychiatric disorders (Dedic et al., 2018).

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(Hu, Liang, & Soong, 2017)

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The studies aim was to analyse how CACNA1C modifies the risk to psychiatric disorders following developmental and environmental factors using both genetic mouse models and human data.

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Would stress vulnerability also be differentially affected upon deletion of the calcium channel in adulthood? 

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Would stress vulnerability also be differentially affected upon deletion of the calcium channel in adulthood? 

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To investigate this, the researchers conducted the following experiments:
(A) Open Field Test
(B) Dark/Light Box Test
(C) Sociability Test
(D) Forced Swim Test
(E) Spatial Object Recognition Test

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In contrast to Cav1.2Het mice, locomotion/exploration in the open field test was only decreased in the stressed control but NOT in the stressed Cav1.2-AdGlu-CKO mice.

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In contrast to developmental deletion, when the calcium channel is deleted in adulthood, the CKO mice display enhanced resilience to CSDS by demonstrating decreased anxiety. The CKO mice spent more time in the lit zone, have more lit zone entries and have a lower latency to 1st lit zone entry.

Control mice responded to CSDS with increased anxiety in these tests. Contrastingly, CKO mice performed better, signifying enhanced resilience to CSDS..

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In the sociability test, the control mice perform better than the CKO in both cases, basal and stressed. This demonstrated that the control mice interact with more mice and therefore perform better than CKO mice.

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Forced swim test was done to test immobility and the CKO mice proved to be less immobile in both conditions and therefore performed better. This indicates that they are more hyperactive and struggle more implying increased active stress-coping behaviour.

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Spatial object recognition test was done and under basal conditions both Ctrl and CKO mice performed the same. However, under stressed conditions, CKO mice performed better.

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It is fair to approach conclusions gained in model organisms with scrutiny when applied to humans. After all, it is impossible to model whole psychological disorders in a mouse, only certain characteristics and behaviours known to be linked to that disorder (Robertson et al., 2011). In the Dedic et al., 2018 human cohort, CACNA1C showed that certain SNPs could predict depressive symptoms in human trauma victims. Further GWAS studies have connected CACNA1C to risk for psychiatric disorders (Moon et al., 2018).  There seems to be a link between neuropathy and CACNA1C in humans as well as mice. This has great implications for diagnosis of disorders and treatment through personalized psychiatry.

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Dedic et al., 2018 is very well supported by other works in the area of neuropathy.  Works such as Klausa et al., 2018 have researched the impacts of early life stress and CACNA1C in cortisol levels. Research done in Kisko et al., 2018 showed that CACNA1C haploinsufficiency was detrimental to the socio-affective communication of rats, linking it to autism, bipolar disorder, and schizophrenia. The difference in effect of adult vs embryonic deletion of CACNA1C has been replicated in other studies as well (Michels et al., 2018).

As scientists begin to probe into the physiological functions of CACNA1C maintain the link between CACNA1C and neuropathy. The results of studies such as Michels et al., 2018 show that CACNA1C protects against oxidative stress at the level of the nervous system, a condition that has long been associated with neuropathic disorders. While research into Ca V 1.2 is ongoing and no molecular pathway has been detailed yet Ca V 1.2 is known to mediate transcription, cell survival, and synaptic plasticity (Michels et al., 2018).

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Several limitations exist in this study. Many trials were performed without sample sizes being provided. Small sample sizes or missing results can be high sources of bias. When sample size is not reported the reader cannot determine for themselves if good research has been performed. Furthermore, Dedic et al., 2018 used a highly traumatised group of mostly African Americans for the human cohort. This is not representative of a diverse human population. Finally, psychiatric disorders can sometimes be hard to characterize since many exist on a spectrum. While mouse models can, and have, accurately depicted the characteristics of many psychiatric disorders they cannot completely capture the true complexity of every human experience of the disorder it’s spectrum (Robertson et al., 2011).

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There appears to be a large difference in the results of embryonic compared to adult mice that had the CACNA1C gene deleted. CKO adult mice were shown to have done better in spatial object recognition under stress than control mice whereas comparisons for embryonic mice had no significant results. Although CACNA1C plays the same overall role on mice and neurological disorders, why does certain traits vary so much? Is it possible then that a deletion of CACNA1C in adults can one day be used to help humans cope with anxiety and other stress related disorders?
Although this article is quite current, new studies have already come out claiming that although CACNA1C is a risk gene variant for neurological disorders such as SZ and BP, it mainly only effects females (Takeuchi et al). This is interesting since the original article didn't say anything about the variation in gender. Additionally, SZ is known to be more common in males so the fact that this gene appears to pose a greater risk to females is quite novel. The role of CACNA1C has also been recently linked to 5-HT which is a serotonin receptor. Through a specific 5-HT CACNA1C knockout, it was seen that normal activity can be restored by blocking the 5-HT1A receptors.

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Bhat, S., Dao, D. T., Terrillion, C. E., Arad, M., Smith, R. J., Soldatov, N. M., & Gould, T. D. (2012). CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Progress in Neurobiology, 99(1), 1–14. https://doi.org/10.1016/j.pneurobio.2012.06.001

Bora, E., & Berk, M. (2016). Theory of mind in major depressive disorder: A meta-analysis. Journal of Affective Disorders, 191, 49–55. https://doi.org/10.1016/j.jad.2015.11.023

Cardno, A. G., & Owen, M. J. (2014). Genetic relationships between schizophrenia, bipolar disorder, and schizoaffective disorder. Schizophrenia Bulletin, 40(3), 504–515. https://doi.org/10.1093/schbul/sbu016

Dedic, N., Pöhlmann, M. L., Richter, J. S., Mehta, D., Czamara, D., Metzger, M. W., …   Deussing, J. M. (2018). Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood. Molecular psychiatry, 23(3), 533–543. https://doi.org/10.1038/mp.2017.133

Ehlinger DG, Commons KG. Cav1.2L-type calcium channels regulate stress coping behaviour via serotonin neurons. Neuropharmacology. 2018 Sept 1;144:282-290

Geddes, J. (2003). Bipolar disorder Bipolar disorder. Lithium, 346(February 2008), 6–8. https://doi.org/10.1016/S0140-6736(15)00241-X

Green EK, Grozeva D, Jones I, Jones L, Kirov G, Caesar S et al. (2009) The bipolar disorder risk            allele at CACNA1C also confers risk of recurrent major depression and of      schizophrenia. Mol Psychiatry; 15:1 -7

Hu, Z., Liang, M. C., & Soong, T. W. (2017). Alternative Splicing of L-type CaV1.2 Calcium        Channels: Implications in Cardiovascular Diseases. Genes, 8(12), 344. https://doi.org/10.3390/genes8120344

Klausa, K., Butlera, K., Gutierrezb, H., Durranta, S.J., Pennington, K. (2018) Interactive effects of early life stress and CACNA1C genotype on cortisol awakening response. Biological Psychology, 136(1), 22-28. https://doi.org/10.1016/j.biopsycho.2018.05.002

Kisko, T.M., Braun, M.D., Michels, S., Witt, S.H., Rietschel, M., Culmsee, C., Schwarting R.K.W., Wöhr, M. (2018) Cacna1c haploinsufficiency leads to pro-social 50-kHz ultrasonic communication deficits in rats. Disease Models & Mechanisms. doi: 10.1242/dmm.034116

Michels, S., Wöhr, M., Schwarting, R.K.W., Culmsee, C., (2018) Psychiatric risk gene Cacna1c determines mitochondrial resilience against oxidative stress in neurons. Cell Death & Disease, 645(9). DOI 10.1038/s41419-018-0676-9

Moon, A.L., Haan, N., Wilkinson, L.S., Thomas, K., Hall, J. (2018) Schizophrenia Bulletin, 44(5), 958-965. doi:10.1093/schbul/sby096

Owen, J Sawa, A Mortensen, PB (2009) Schizophrenia. Lancet; 388 (10039), 86-97. Doi:            10.1016/S0140-6736(15)01121-6

Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA et al. (2011)         Genomewide association study identiﬁes ﬁve new schizophrenia loci. Nat Genet ;          43: 969–976.

Robertson, H.R., Feng, G. (2011) Annual Research Review: Transgenic mouse models of childhood-onset psychiatric disorders Journal of Child Psychology and Psychiatry, 52(4), 442-475. doi: 10.1111/j.1469-7610.2011.02380.x

Smoller JW. (2013) Identiﬁcation of risk loci with shared effects on ﬁve major psychiatric disorders: a genome-wide analysis. Lancet 2013; 381: 1371 –1379

Takeuchi H, Tomita H, Taki Y, Kikuchi Y, Ono C, Yu Z, Nouchi R, Yokoyama R, Kotozaki Y, Nakagawa S, et al. A common CACNA1C gene risk variant has sex dependent effects on behavorial traits and brain functional activity. Cereb Cortex. 2018 Aug 15.

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Dopamine has been studied in a large amount for neurological disorders, predominately SZ. However since studies have found that 5-HT can play a role in regulating behaviour after CACNA1C deletion, more studies should be done to study the effects of serotonin on neurological disorders and regulation of the gene/Cav1.2 channel. There should also be considerations in gender as well as age of mice as those proved to be factors which are not always consistent in previous studies. Although these are ways that  regular behaviour can be re-established, studies have yet to look into if they can be applied to a grand scope of neurological disorders.

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Cav1.2-DevGlu-CKO mice showed poor accuracy levels that did not surpass chance level of 50%. Drastic cognitive decline was observed.

They performed the WCM test to investigate spatial navigation, which relies on memory and learning. here, the authors assessed accuracy, or how accurately the mice found the correct platform. Cav1.2-DevGlu-CKO mice displayed accuracy levels that barely reached the chance level of 50%, suggesting drastic cognitive decline. This occurred in both the learning phase (week1) and the re-learning phase, week 2.

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Table1 displays a summary of the main results. The embryonic deletion of CACNA1C promoted endophenotypes of several psychiatric disorders such as anxiety disorders, major depressive disorders (MDD) and Schizophrenia. They observed cognitive decline, hyperactivity and increased anxiety.
Moreover, the depletion of CACNA1C during development increased susceptibility to chronic stress, suggesting that the endophenotypes interacted with the environment to shape disease vulnerability. We will later see that there is some specificity to this vulnerability.
However, deletion of the calcium channel in adulthood rather than during development, yielded surprising results. There was found to be an enhanced resilience to CSDS in Cav1.2-AdGlu-CKO mice. Dark/light box tests were used to test for anxiety and it revealed that the Cav1.2-AdGlu-CKO mice displayed decreased anxiety.

The authors performed different tests to determine if they would observe behavioural endophenotypes known to be altered in animal models of MDD, BPD and SCZ, such as hyperactivity observed in manic phases of BPD or enhanced anxiety in MDD

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Decreased preference to interact with other mice.

Different neuropsychiatric disorders display disruptions in social behavior. Here, KO mice display decreased preference for the social counterpart in the sociability test, as they spend a lower percentage of time interacting with it.

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(V) The Relation Between CACNA1C Deletion And CSDS

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(V) The Relation Between CACNA1C Deletion And CSDS

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The heterozygous mice displayed increased anxiety in the box test, evident by decreased time spent in the lit zone, lower number of entries and a much greater latency to enter it.

However, the effect on vulnerability may be specific, as there was no sig effect on sociability, since the stress groups spent sim amount of time int w the social counterpart, no significant difference between active stress-coping as stress groups showed similar immobility levels in the forced swim test and there was no differential effect on memory, as stress groups spent same amount of time int with the displaced object.