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. 2016 Apr 24;594(20):5823–5837. doi: 10.1113/JP270673

L‐type Ca2+ channels in mood, cognition and addiction: integrating human and rodent studies with a focus on behavioural endophenotypes

Z D Kabir 1,2,3, A S Lee 1,2,3, A M Rajadhyaksha 1,2,3,✉
PMCID: PMC5063939  PMID: 26913808

Abstract

Brain Cav1.2 and Cav1.3 L‐type Ca2+ channels play key physiological roles in various neuronal processes that contribute to brain function. Genetic studies have recently identified CACNA1C as a candidate risk gene for bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder (MDD) and autism spectrum disorder (ASD), and CACNA1D for BD and ASD, suggesting a contribution of Cav1.2 and Cav1.3 Ca2+ signalling to the pathophysiology of neuropsychiatric disorders. Once considered sole clinical entities, it is now clear that BD, SCZ, MDD and ASD share common phenotypic features, most likely due to overlapping neurocircuitry and common molecular mechanisms. A major future challenge lies in translating the human genetic findings to pathological mechanisms that are translatable back to the patient. One approach for tackling such a daunting scientific endeavour for complex behaviour‐based neuropsychiatric disorders is to examine intermediate biological phenotypes in the context of endophenotypes within distinct behavioural domains. This will better allow us to integrate findings from genes to behaviour across species, and improve the chances of translating preclinical findings to clinical practice.

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Abbreviations

ASD

autism spectrum disorder

BD

bipolar disorder

BDNF

brain derived neurotrophic factor

CPP

conditioned place preference

DHP

dihydropyridine

FST

forced swim test

GWAS

genome‐wide association studies

LTCCs

L‐type Ca2+ channels

MDD

major depressive disorder

NAc

nucleus accumbens

PFC

prefrontal cortex

PTSD

post‐traumatic stress disorder

SCZ

schizophrenia

SNP

single nucleotide polymorphism

SVF

semantic verbal fluency

VTA

ventral tegmental area

Introduction

Recent human genetic studies have raised tremendous interest and excitement for a role of brain voltage‐gated Cav1.2 and Cav1.3 L‐type Ca2+ channels (LTCCs) in neuropsychiatric and neurodevelopmental disorders. Genome‐wide association studies (GWAS) have linked multiple single nucleotide polymorphisms (SNPs) in the CACNA1C and CACNA1D genes to neuropsychiatric disorders (Bhat et al. 2012; Cross‐Disorder Group et al. 2013; Heyes et al. 2015). Several CACNA1C SNPs, and in particular SNP rs1006737 (risk A allele), have been widely reproduced and strongly associated with bipolar disorder (BD) (Ferreira et al. 2008), major depressive disorder (MDD) (Green et al. 2010; Casamassima et al. 2010 b), schizophrenia (SCZ) (Green et al. 2010; Nyegaard et al. 2010) and recently also autism spectrum disorder (ASD) (Li et al. 2015). CACNA1D SNPs have been linked to BD (Ament et al. 2015). Additionally, variants in coding regions of CACNA1C cause Timothy syndrome, a syndromic ASD (Splawski et al. 2004), and coding variants in CACNA1D have been associated with ASD (O'Roak et al. 2012; Pinggera et al. 2015). The contribution of CACNA1C and CACNA1D SNPs to the pathology of neuropsychiatric disorders is further underscored by their presence in biological pathways implicated in these disorders (Psychiatric GWAS Consortium et al. 2011; Network and Pathway Analysis Subgroup et al. 2015).

Cav1.2 and Cav1.3 channels are important mediators of Ca2+ entry into excitable cells such as neurons. They are both expressed in neurons, with Cav1.2 expressed at higher levels compared to Cav1.3 in the forebrain (Hell et al. 1993) and Cav1.3 serving as the primary LTCC in the midbrain (Rajadhyaksha et al. 2004; Day et al. 2006). They shape neuronal firing and are present in signalling complexes (Calin‐Jageman & Lee, 2008; Zamponi et al. 2015) primarily at the postsynaptic membrane (Di Biase et al. 2008; Jenkins et al. 2010), where they are poised for excitation–transcription coupling (Ma et al. 2012) by activation of Ca2+ second messenger pathways (Simms & Zamponi, 2014) (Fig. 1). Because of these properties, LTCCs play an important role in neuronal plasticity related to neuronal development, learning and memory, drug addiction, and neuropsychiatric illness (Casamassima et al. 2010 a; Bhat et al. 2012; Berger & Bartsch, 2014). Additionally, L‐type activated signal transduction pathways crosstalk with dopamine and glutamate signalling pathways (Rajadhyaksha & Kosofsky, 2005), important mediators of neuronal processes underlying the neuropathology of multiple brain disorders. (For more in‐depth information, readers are directed to Casamassima et al. 2010 a; Bhat et al. 2012; Berger & Bartsch, 2014; Simms & Zamponi, 2014; Striessnig et al. 2014; Zamponi et al. 2015).

Figure 1.

Figure 1

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Schematic diagram of the L‐type Ca2+ channels Cav1.2 and Cav1.3, and β and α2δ auxiliary subunits

Given the importance of Cav1.2 and Cav1.3 channels in brain function and the recent human genetic findings establishing CACNA1C and CACNA1D as risk genes for neuropsychiatric disorders, the time is prime to structure scientific studies to begin to identify the biological effects of human genetic variants that are reliable and eventually translatable back to the patient. This requires detailed analyses across multiple levels of complexity from gene to molecule to cell to circuit and behaviour. This is particularly important when studying neuropsychiatric disorders that clinically are behaviour‐based disorders. Additionally, neuropsychiatric disorders (such as BD, SCZ and ASD), once considered unitary entities, share common behavioural phenotypic features most likely due to overlapping neurocircuitry (the primary focus of this review; Millan et al. 2012; Luthi & Luscher, 2014). Thus, the emphasis on utilizing behavioural domains (endophenotypes) as opposed to clinical diagnosis, as proposed in the Research Domain Criteria Framework (RDoC) by the National Institute of Mental Health (NIMH) (Insel, 2014), to explore the impact of CACNA1C and CACNA1D human polymorphisms on neuronal function and on neuronal circuits can be greatly helpful. We believe that such an approach will allow the integration of information from molecule to behaviour and increase the chance of translation of biological findings across species (human to mouse and back to human), towards better treatment outcomes in patients. Such an approach is already underway in multiple laboratories. The availability of new molecular and genetic technologies to study cacna1c and cacna1d in rodent models and the availability of samples derived from patients (such as patient brain tissue and patient‐derived induced pluripotent cells) have already begun to shed light on the contribution of human cacna1c genetic variants on the pathophysiology of disease.

There have been several excellent recent reviews on Cav1.2 and Cav1.3 LTCCs in brain and brain disorders (Casamassima et al. 2010 a; Bhat et al. 2012; Berger & Bartsch, 2014; Striessnig et al. 2014; Zamponi et al. 2015). In this review we aim to integrate recent human behavioural and neuroimaging data with information available from preclinical cacna1c and cacna1d rodent models to begin to gain insight on how dysfunction of Cav1.2 and Cav1.3 channels at the level of brain anatomy and circuitry can lead to behavioural phenotypes associated with neuropsychiatric disease. We hope that this will encourage electrophysiological, cellular and molecular studies in the context of neuropsychiatric‐related behavioural deficits.

Integrating human and mouse findings to understand pathological circuitry underlying intermediate phenotypes of psychiatric disorders

To date, the CACNA1C SNPs linked to neuropsychiatric disorders are present within non‐coding regions (intronic, 5′ and 3′ untranslated regions) (Bhat et al. 2012) suggesting that they would affect CACNA1C gene expression. Consistent with this, both an increase (Bigos et al. 2010; Yoshimizu et al. 2015) and decrease (Gershon et al. 2014; Roussos et al. 2014; Yoshimizu et al. 2015) in CACNA1C mRNA have been reported in human samples (brain tissue and induced pluripotent stem cell (iPSC)‐derived neurons), suggesting that gain or loss of Cav1.2 function can be detrimental. Cav1.2 gain of function mutation causes Timothy syndrome and CACNA1D single nucleotide variants identified in ASD (O'Roak et al. 2012) have recently been shown to be gain of function variants (Pinggera et al. 2015).

Brain imaging and clinical studies in the most replicated CACNA1C neuropsychiatric risk SNP rs1006737 has revealed altered brain structure and function in healthy carriers and patients (Bhat et al. 2012; Berger & Bartsch, 2014), underscoring the functional contribution of CACNA1C to the neuropathology underlying neuropsychiatric disorders.

Rodents (in particular mice) have proved to be useful in exploring human behavioural deficits, specifically for mapping circuitry that underlies behavioural phenotypes. Additionally humans and rodents share emotional behaviours and emotional circuitry that are conserved from mouse to human (Janak & Tye, 2015), thus allowing translation of human polymorphisms to mouse and back to the human. This has been elegantly demonstrated for a polymorphism in the BDNF gene (Glatt & Lee, 2015), a downstream molecular target of LTCCs (Tao et al. 1998; Tabuchi et al. 2000). At this time, studying CACNA1C non‐coding variants in mouse models poses a challenge. However, studying loss of function (such as the use of knockout mice; Moosmang et al. 2005; Dao et al. 2010; Lee et al. 2012) or gain of function (such as the Timothy syndrome mouse model; Barrett & Tsien, 2008; Bader et al. 2011) can be informative.

To begin to gain a greater understanding of the Cav1.2 and Cav1.3 mediated neural mechanisms underlying the pathophysiology of psychiatric disorders, we attempt to integrate anatomical and circuit information that has been obtained from human neuroimaging and clinical studies with findings reported in cacna1c and cacna1d mouse models in the context of the major behavioural endophenotypes of neuropsychiatric disorders (mood and emotion, cognition, and social, in addition to addiction, a co‐morbid endophenotype) associated with the CACNA1C and CACNA1D risk genetic variants.

Mood and emotion

CACNA1C

Changes in mood and emotion are core features that underlie psychiatric disorders. These can be manifested as anxiety and depression that are prominent components of the forms of neuropsychiatric disease in which CACNA1C has been implicated. Interestingly, healthy CACNA1C rs1006737 risk allele carriers had significantly higher scores for depression and anxiety on a self‐report questionnaire (Erk et al. 2010, 2014 a). These findings were replicated in a separate cohort of CACNA1C rs1006737 risk‐allele healthy individuals who displayed increased trait anxiety and proneness to depression (Roussos et al. 2011).

Additionally, dysregulation of negative emotions, such as fear, also forms a core component underlying anxiety disorders (Dymond et al. 2014; Singewald et al. 2015). Human and rodent studies have revealed overlapping circuitry underlying fear, anxiety and depression. Fear‐associative learning protocols have proven to be extremely useful to examine the neurocircuitry underlying anxiety disorders (Hijzen et al. 1995; Ohl et al. 2003; Singewald et al. 2015). In humans and rodents, fear conditioning is a form of emotional learning in which a naturally aversive stimulus (unconditioned) is paired either with a neutral context (contextual‐associated) or tone (cue‐associated) to elicit a fear response measured as freezing behaviour in rodents, or a physiological response in humans. Emotional responses to facial expressions (e.g. fearful faces, happy faces) are additionally used in humans to evaluate emotional processing (Ekman, 1992). In humans, a startle response is often used to measure negative emotional processing during visualization of unpleasant pictures (Lissek et al. 2007; Anokhin & Golosheykin, 2009; Fendt & Koch, 2013). In both humans and rodents, the inability to extinguish the conditioned context or cue fear response is additionally utilized to evaluate dysregulated fear (rodents) and emotional (humans) processing (VanElzakker et al. 2014) as observed in patients with SCZ and post‐traumatic stress disorder (PTSD), an anxiety disorder.

Using fear‐learning protocols, the amygdala, prefrontal cortex (PFC) and hippocampus have been established as the primary fear circuit in both humans and rodents (Phelps & LeDoux, 2005; Sehlmeyer et al. 2009). The amygdala is critical for the acquisition and expression of a conditioned fear response in rodents (LeDoux, 2003; Keifer et al. 2015) and humans (LaBar et al. 1995; Hamm & Weike, 2005). The PFC exerts a top‐down regulation of the amygdala while the hippocampus, with its regional connectivity, can provide a modulatory effect on the amygdala either directly or via the PFC. The hippocampus functions to influence the context‐dependent expression of fear (Knight et al. 2004; Sierra‐Mercado et al. 2011; Sotres‐Bayon et al. 2012), the extinction of cue‐associated fear memories in rodents (Sierra‐Mercado et al. 2011; Maren et al. 2013; Rosas‐Vidal et al. 2014), and the extinction recall of contextual‐associated fear memories in humans (Kalisch et al. 2006; Milad et al. 2007; Ahs et al. 2015). The use of optogenetic studies in rodents has also established the PFC, amygdala and hippocampus in regulating anxiety and depression (Covington et al. 2010; Tye et al. 2011; Warden et al. 2012; Ota et al. 2014; Bagot et al. 2015). In depressed patients, structural and functional alterations in these regions have been reported (Busatto, 2013).

Consistent with a role of the PFC–amygdala–hippocampus circuit in anxiety, depression and fear, neuroimaging studies in both healthy CACNA1C risk allele carriers (rs1006737 having been studied the most to date) and in patients, have identified structural and functional alterations within this circuit (Fig. 2). Structural neuroimaging studies have revealed that CACNA1C rs1006737 risk allele carriers have increased grey matter density in the PFC (Wang et al. 2011) and right amygdala (Perrier et al. 2011), and altered white matter microstructure in the right hippocampal formation (Dietsche et al. 2014). Functional imaging studies have found increased activation in the amygdala and ventral PFC of CACNA1C rs1006737 risk allele carriers during facial affect processing (Dima et al. 2013). Similar findings were obtained in two other independent studies that observed increased activity in the left amygdala during a negative face matching task in both healthy individuals (Jogia et al. 2011; Tesli et al. 2013) and BD patients that carry the CACNA1C rs1006737 risk allele (Tesli et al. 2013). Additionally at the circuit level, Wang et al. (2011) reported decreased functional connectivity between the PFC and amygdala during a facial processing task (fearful and happy faces) in CACNA1C rs1006737 risk allele carriers (Wang et al. 2011). In BD patients that were carriers of the CACNA1C rs1006737 risk allele, Radua et al. (2012) reported decreased outflow of the medial frontal gyrus to the left putamen (part of the striatum) during perception of fearful faces, demonstrating hypo‐connectivity between a prefrontal cortical region and a limbic structure during emotional processing (Radua et al. 2012).

Figure 2. Overlapping neurocircuitry of L‐type Ca2+ channels contributing to endophenotypes of psychiatric disorders .

Figure 2

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Single arrow denotes unidirectional connectivity in the direction of the arrow and double arrow denotes bidirectional connectivity. PFC, prefrontal cortex; HPC, hippocampus; STR, striatum; NAc, nucleus accumbens; AMG, amygdala; VTA, ventral tegmental area.

Similarly in the hippocampus of CACNA1C risk allele carriers, Bigos et al. (2010) reported increased hippocampal activity in healthy individuals who were homozygote for the CACNA1C rs1006737 risk allele (AA), when measured during a facial processing task (Bigos et al. 2010). In a separate study Erk et al. (2010) showed a significant negative correlation between regional activation in the hippocampus and depression and anxiety scores (Erk et al. 2010) that was confirmed in a later study (Erk et al. 2014 a). Data from these human neuroimaging studies provide clear evidence of structural and functional alterations in the PFC–amygdala–hippocampus circuit as a consequence of the CACNA1C risk allele. The dysregulation of this circuit has been suggested to be the underlying factor modulating the anxiety and depression intermediate phenotypes commonly observed in BD, SCZ and MDD (Erk et al. 2014 b). With regard to the behavioural effects of the CACNA1C rs1006737 risk allele on emotional processing a study by Pasparakis et al. (2015) found reduced affective startle responses to pleasant pictures and exaggerated responses to negative pictures in healthy CACNA1C rs1006737 risk allele carriers (Pasparakis et al. 2015), further supporting the impact of the CACNA1C risk allele on the PFC–amygdala–hippocampus circuit.

In contrast to the human literature there have been few, but significantly important, animal studies that have begun to dissect the role of cacna1c (Cav1.2) in anxiety, depression and fear and their underlying neurocircuitry. To study anxiety in rodents, behavioural protocols that use approach–avoidance conflict to inhibit an ongoing behaviour that is characteristic for the animal have been utilized (Bailey & Crawley, 2009) and include the open‐field test, light–dark test and the elevated plus maze test (Ohl et al. 2003). Using these tests, constitutive heterozygous cacna1c knockout female (Dao et al. 2010) and male mice (Bader et al. 2011; Lee et al. 2012) have been shown to exhibit increased anxiety‐like behaviour. The anxiety phenotype was recapitulated in conditional cacna1c‐deficient male mice that had cacna1c knocked out specifically in excitatory neurons of the forebrain (Lee et al. 2012). Additionally consistent with altered PFC function in CACNA1C risk allele carriers, focal deletion of cacna1c in the PFC of adult mice resulted in an anxiogenic phenotype (Lee et al. 2012). Interestingly, the knock‐in Cav1.2 gain of function TS mouse displayed no alteration in anxiety (Bader et al. 2011). As human studies have revealed altered function of the amygdala and hippocampus in CACNA1C risk allele carriers, additional rodent studies using strategies such as focal deletion of Cav1.2 in these regions would be greatly helpful in elucidating the cacna1c neural circuitry underlying anxiety.

Studying depression in rodents is accomplished using behavioural protocols like the Porsolt forced swim test (FST) (Porsolt et al. 1977; Can et al. 2012), tail suspension test (Bergner et al. 2010) and the sucrose preference test (Katz, 1982; Strekalova et al. 2004) that target the core components of depressive‐like behaviour such as despair (FST and tail suspension test) and anhedonia (sucrose preference test). So far, only one study has been published reporting an anti‐depressive phenotype in constitutive cacna1c heterozygous mice using FST and the tail suspension test (Dao et al. 2010). We have replicated this finding using FST and the sucrose preference test (authors’ unpublished observations) and ongoing studies in our laboratory are currently examining the anatomical and molecular mechanisms mediating the anti‐depressive phenotype in constitutive cacna1c heterozygous mice.

As the behavioural paradigm and underlying neurocircuitry in fear‐learning has been well established, several researchers have focused their attention on the role of Cav1.2 channels in fear processing. Interestingly, conditional knockout of cacna1c in the excitatory neurons of the forebrain had no effect on the conditioning or extinction of a contextual‐associated fear memory (McKinney et al. 2008). Langwieser et al. (2010) similarly found no deficit in the consolidation and recall of a cue‐associated fear memory in brain specific cacna1c knockout mice and identified that the lack of this particular phenotype was a result of compensatory upregulation of Ca2+ permeable glutamate AMPA receptors in the amygdala (Langwieser et al. 2010). Thus, compensatory adaptations in developmental knockout mouse models may override the influence of Cav1.2 LTCCs in fear conditioning protocols and may not be the most appropriate option to study the role of these channels in fear processing. This is highlighted from pharmacological studies where acute inhibition of LTCCs with an LTCC blocker (isradipine or verapamil) delivered either into the intracerebroventricular compartment (Langwieser et al. 2010) or directly into the lateral division of the amygdala (Bauer et al. 2002) of the adult animal was sufficient to induce a deficit in recall of a cue‐associated fear memory. Similarly repeated inhibition of LTCCs with verapamil or nifedipine in the basolateral amygdala of the adult rat impaired cue fear extinction, demonstrating that LTCCs can mediate fear processing (Davis & Bauer, 2012). As pharmacological blockers to date do not differentiate between the two LTCC isoforms, Cav1.2 and Cav1.3, we encourage alternative strategies such as the use of focal brain knockout of Cav1.2 in the adult brain using viral vectors (Lee et al. 2012) to directly test the role of the Cav1.2 LTCCs in fear memory recall. This suggestion is underscored by the finding that knockout of Cav1.2 channels using viral vectors specifically in the anterior cingulate cortex, a brain region that has increased activity during the observation of others’ fear (Olsson et al. 2007), impaired observational fear learning in mice (Jeon et al. 2010). This further suggests that the Cav1.2 isoform can be recruited during fear learning and highlights the importance of examining site‐targeted deletion of these channels. Further support of the role of Cav1.2 in fear processing is provided from the knock‐in Timothy syndrome mouse that displayed significantly increased contextual‐ and cue‐associated fear memories that persisted up to 2 weeks postconditioning (Bader et al. 2011).

Contextual‐associated fear memories are dependent not only on the amygdala but also on the hippocampus that is recruited to form a representation of the fear‐associated context (Phillips & LeDoux, 1992). Since conditional cacna1c knockout mice display a deficit in recall of a hippocampal‐dependent spatial memory 30 days after training (White et al. 2008), it begs the question on whether these mice have a similar deficit in long‐term contextual‐associated fear memories, an area of study that has not been as extensively explored but is highly relevant with regard to PTSD.

CACNA1D

Mouse models of cacna1d have been utilized to study the role of the Cav1.3 LTCCs in anxiety (Lee et al. 2012), depressive‐like behaviour (Sinnegger‐Brauns et al. 2004) and fear processing (McKinney & Murphy, 2006). We have previously shown that focal knock‐down of Cav1.3 in the PFC does not impact anxiety (Lee et al. 2012), ruling out the role of these channels in the PFC in mediating anxiety‐like behaviour. When tested in FST, Cav1.3 knockout mice exhibit an antidepressive‐like phenotype. Using Cav1.2 dihydropyridine (DHP)‐insensitive mutant mice that have a point mutation in the DHP‐binding pocket of the Cav1.2 subunit eliminating the sensitivity of the Cav1.2 channels to DHP blockers, when treated with the DHP LTCC activator BayK8644 resulted in a depressive‐like behavioural phenotype (Sinnegger‐Brauns et al. 2004), suggesting a role for Cav1.3 LTCCs in the modulation of depressive‐like behaviour. In contextual fear conditioning, homozygous cacna1d knockout mice display impaired consolidation of fear memory but normal extinction (McKinney & Murphy, 2006). Given the recent finding of compensatory adaptation in cacna1d knockout mice (Poetschke et al. 2015), the Cav1.2 DHP insensitive mutant mouse line is an excellent mouse model to further explore the role of Cav1.3 channels in fear processing, in addition to the use of viral vectors expressing Cav1.3 short hairpin (sh)RNA (Schierberl et al. 2011 a; Lee et al. 2012).

Cognition

Although alterations in mood and emotion form the main components in neuropsychiatric disorders, deficits in cognition are commonly observed and can be equally debilitating to the lifestyle of an individual (Millan et al. 2012). Several human studies have shown an association between the CACNA1C rs1006737 risk variant and cognitive function. In healthy individuals there are conflicting results over the influence of this gene on cognitive function. Some studies report lower verbal fluency performance (Krug et al. 2010), deficits in attention (Thimm et al. 2011), impaired working memory (Zhang et al. 2012) and poorer learning performance (Dietsche et al. 2014). In contrast, others have reported no significant association between the rs1006737 risk allele in the CACNA1C gene and verbal learning and memory, verbal intelligence (Erk et al. 2010, 2014 a; Roussos et al. 2011), recognition memory (Dietsche et al. 2014), working memory (Paulus et al. 2014) and overall cognitive function (Hori et al. 2012; Soeiro‐de‐Souza et al. 2013). However, in BD and SCZ patients, all studies to date have reported a negative effect of the CACNA1C rs1006737 risk allele on executive function (Arts et al. 2013; Soeiro‐de‐Souza et al. 2013) and working memory (Zhang et al. 2012).

Abnormal neural activity in cortical anatomical regions and concurrent dysregulation in their connectivity to other brain regions have been suggested to be responsible for deficits in cognitive function (Millan et al. 2012) (Fig. 2). From animal studies, it has been shown that the PFC is the central anatomical structure mediating high‐order cognitive function by exerting a top‐down executive control on subcortical structures including the hippocampus, striatum, thalamus and amygdala (Miller, 2000; Riga et al. 2014). Depending on the subcortical structure innervated, the impact of the PFC on distinct cognitive domains varies.

Several functional imaging studies in CACNA1C rs1006737 risk allele carriers have identified alterations in brain activation during multiple cognitive behavioural tasks. During an n‐back working memory task, healthy CACNA1C risk AA homozygote individuals displayed significantly increased activity in the PFC, which they suggested indicated an inefficiency of the PFC (Bigos et al. 2010). In contrast to these findings two separate studies showed that healthy carriers of the CACNA1C rs1006737 risk allele had significantly reduced activation in the dorsolateral PFC during an associative episodic memory task (Erk et al. 2014 a) and the n‐back working memory task (Paulus et al. 2014) with altered connectivity between the dorsolateral PFC and hippocampus (Paulus et al. 2014). In the hippocampus, three independent studies have reported significantly lower activation of the hippocampus in healthy carriers of the CACNA1C rs1006737 risk allele during an episodic memory recall test (Erk et al. 2010, 2014 a,b; Krug et al. 2014) with diminished functional coupling between the left and right hippocampal regions (Erk et al. 2010). Concurrent with this the authors reported decreased activation in the subgenual part of the perigenual anterior cingulate, a brain region that is implicated in mood regulation as well as memory processing (Erk et al. 2014 a,b). Consistent with lower verbal fluency in CACNA1C rs1006737 risk allele carriers (Krug et al. 2010), a test used to measure executive control (Shao et al. 2014), the same study reported increased activation in the left inferior frontal gyrus and left precuneus during a semantic verbal fluency (SVF) task in risk carriers (Krug et al. 2010), while in depressed patients with the CACNA1C rs1006737 risk allele there was increased SVF task‐related activation in the left middle/inferior frontal gyrus and enhanced functional coupling between the left middle/inferior and right superior/middle frontal gyri (Backes et al. 2014).

In the last several decades, distinct behavioural tasks have been developed in animal models to study the underlying neurocircuit and molecular pathways mediating different domains within cognition. To relate these animal models to the deficits in executive function observed in human neuropsychiatric patients, researchers have designed behavioural protocols to mimic the behaviours often used in human studies. Using behavioural tasks in which stimuli are separated in time such as trace fear conditioning (Gilmartin et al. 2013) and the delayed radial arm maze (Floresco et al. 1999), working memory has been shown to be mediated by the prefrontal modulation of the striatum and thalamus (Floresco et al. 1999; Gilmartin et al. 2013). With regard to spatial learning and memory, which has been considered to be equivalent to human declarative abilities (Morellini, 2013), a form of memory that is often disrupted in SCZ (Cirillo & Seidman, 2003), BD (van Gorp et al. 1999) and MDD (Austin et al. 2001), animal behavioural tasks like the Morris water maze, the radial arm maze and spontaneous alternation in the T maze have been utilized to demonstrate the involvement of the PFC, hippocampus and dorsal striatum (Morellini, 2013; Pooters et al. 2015). Another domain within cognition that has often been reported in neuropsychiatric disorders is cognitive flexibility, defined as the ability to flexibly alternate one's behaviour in response to changing environmental contingencies. In humans, this has been measured using the Wisconsin card‐sorting task (Miyake et al. 2000) and the Stroop test (Jensen & Rohwer, 1966) while in animal models this has been tested through reversal learning in a Y maze (Trinh et al. 2012) or operant task (Brady & Floresco, 2015), as well as through extinction of a conditioned fear (Trinh et al. 2012).

While there is significant, though limited, evidence of the negative relationship between the CACNA1C risk allele and cognition in humans, not much has been done in identifying the neuroanatomical basis of these deficits. To date, only one study has identified a deficit in long‐term (30 day) recall of a spatial memory in mice that had a conditional knockout of cacna1c in the excitatory neurons of the forebrain (White et al. 2008), suggesting a role of these channels in cognition. Similar evidence of a role of these channels in cognition has been obtained through studies done in the knock‐in Timothy syndrome mouse (Bader et al. 2011) that displayed normal learning and memory but significant deficits in reversal learning (Bader et al. 2011). Additional studies need to further explore cacna1c animal models to understand the role of Cav1.2 channels in cognitive deficits.

We believe that it is of high priority to explore Cav1.2 as a potential target for treating cognitive impairments in neuropsychiatric patients particularly since the current drugs used to treat the mood‐related symptoms in psychiatric disorders fail to alleviate the cognitive deficits (Millan, 2006; Hill et al. 2010). Unpublished data from our lab suggest a role for Cav1.2 channels in mediating different aspects of cognition that is interactive with distinct neurotransmitter systems.

Social behaviour

Deficits in social behaviour and communication are observed in a range of neuropsychiatric disorders, including SCZ and depression, and represents a core feature observed in ASD (Kennedy & Adolphs, 2012; APA, 2013). In humans, social interaction is complex and heavily dependent on appropriate cognitive and emotional function. Interestingly, in healthy individuals the CACNA1C rs1006737 risk allele was significantly associated with low extraversion, a personality trait that is characterized by reduced social activities and interactions (Roussos et al. 2011).

As with all the other endophenotypes discussed above social behaviour is mediated by a network of brain regions that function in an interdependent manner (Fig. 2). These include the fusiform gyrus that mediates face perception, the amygdala and anterior cingulate cortex that are involved in processing facial expressions of fear, and the PFC that is required for interpreting others’ intentions and motives (Grady & Keightley, 2002). In CACNA1C rs1006737 risk allele carriers, there is increased activation of the fusiform gyrus during a facial affect‐processing task (Dima et al. 2013), suggesting dysregulation within the circuitry that is recruited for facial processing in social interaction.

Rodents, being innately social creatures, have been used to study social behaviour. Through lesion and optogenetic studies, certain key anatomical regions mediating social behaviour in rodents have been delineated and includes the hippocampus (Felix‐Ortiz & Tye, 2014; Hitti & Siegelbaum, 2014; Stevenson & Caldwell, 2014), amygdala (Martel et al. 2008; Katayama et al. 2009), PFC (Jodo et al. 2010; Yizhar et al. 2011; Felix‐Ortiz et al. 2015), nucleus accumbens (NAc) and ventral tegmental area (VTA) (Gunaydin et al. 2014). In rodents, social behaviour is most commonly studied using the social approach test in a 3‐chamber apparatus in which the time that the test mouse spends interacting with a stranger mouse versus an inanimate object is measured. Reciprocal interactions between pairs of mice are also studied in which a variety of parameters, including nose‐to‐nose interactions, anogenital sniffing, allogrooming and play, are measured (Silverman et al. 2010).

Although the CACNA1C gene has been implicated in ASD and SCZ, both of which show significant impairments in social behaviour, no study to date has tested social behaviour in cacna1c deficient mice. However, the knock‐in Timothy syndrome mouse displays a severe deficit in social behaviour (Bader et al. 2011), demonstrating that Cav1.2 channels can regulate social behaviour. The lack of studies points to a need for additional work to further explore the role of cacna1c in social behaviour. Similarly, because of the recent finding of the association between the CACNA1D gene and ASD (O'Roak et al. 2012; Pinggera et al. 2015), preclinical studies need to be pursued using cacna1d mouse models to identify the impact of this gene on social behaviour.

Reward and addictive behaviour

Altered reward processing and reward brain circuitry is often associated with multiple psychiatric disorders (Pechtel et al. 2013; Whitton et al. 2015). Importantly, substance abuse disorders are often co‐morbid with neuropsychiatric disorders (Post & Kalivas, 2013; Luthi & Luscher, 2014; Lai et al. 2015). Cocaine use in particular has been associated with higher incidence of mood and anxiety disorders (Falck et al. 2004; Post & Kalivas, 2013; Luthi & Luscher, 2014). In a study conducted by Herrero et al. (2008), over 40% of young cocaine users recruited in non‐clinical settings presented psychiatric co‐morbidity, with 27% diagnosed with mood disorders and 13% diagnosed with anxiety disorders (Herrero et al. 2008). Furthermore, the severity of anxiety disorders such as PTSD, MDD and BD may be increased when co‐morbid with substance use disorder (Kessler et al. 2005). Conversely, patients with psychiatric disorders may have an increased vulnerability to abuse drugs. Patients with anxiety disorders, BD and SCZ have an increased likelihood of cocaine and stimulant use (Volkow, 2009; Post & Kalivas, 2013; Tang et al. 2014).

Overlapping neurocircuitry and common genetic risk factors have been suggested to underlie the high co‐morbidity in mood and drug abuse disorders (Nestler & Carlezon, 2006; Luthi & Luscher, 2014). Many studies reveal convergence of neuronal circuits (Fig. 2) and molecular mechanisms involved in mood disorders and reward systems (Peters & Buchel, 2009; Russo & Nestler, 2013; Luthi & Luscher, 2014). The NAc is the key nucleus that modulates reward and motivation for drug seeking (Kelley, 2004; Kalivas & Volkow, 2005), by integrating information from other brain regions within the mesolimbic reward circuitry that include, but are not limited to, dopaminergic inputs from the VTA and glutamatergic inputs from the basolateral amygdala, medial PFC and hippocampus (Koob & Volkow, 2010), identical brain regions also recruited for the intermediate phenotypes discussed above. The VTA additionally projects to the medial PFC, hippocampus and basolateral amygdala (Fig. 2).

In rodents, three commonly used behavioural protocols to assess the addictive potential of drugs of abuse are behavioural sensitization, conditioned place preference (CPP) and self‐administration. Behavioural sensitization is a model of drug‐induced long‐term synaptic and behavioural plasticity (Robinson & Berridge, 1993; Pierce & Kalivas, 1997; Vanderschuren & Pierce, 2010). Interestingly, increased behavioural drug responsivity also occurs as a result of repeated stress and repeated occurrence of episodes of BD (Post & Kalivas, 2013). CPP is a simple, non‐invasive procedure wherein animals are trained to associate a specific environment with the rewarding effects of a drug (Bardo & Bevins, 2000). Subsequently when animals are allowed to freely explore the drug‐paired and non‐drug‐paired environment, they prefer the drug‐paired environment, indicating drug–reward associations. The conditioned response is thought to be relevant to human drug‐seeking behaviour and to drug‐ and cue‐induced relapse (Stewart, 2008). The operant reinstatement model of cocaine seeking using the self‐administration procedure wherein animals volitionally respond for delivery of a drug such as cocaine, possesses greatest face validity as a model of addiction, as it most closely resembles human self‐administered drug taking behaviour (Panlilio & Goldberg, 2007).

Using the above behavioural protocols, pharmacological studies have established an important role of LTCCs in addictive behaviour (reviewed in Bhat et al. 2012; Berger & Bartsch, 2014). Below we specifically highlight what has been found for CACNA1C and CACNA1D in human and mouse.

CACNA1C

To the best of our knowledge, to date human CACNA1C genetic studies in a drug‐dependent population have not been reported. However, as outlined above, several of the brain regions that comprise the brain's reward pathway have altered function in CACNA1C rs1006737 risk allele carriers as revealed by neuroimaging. Two studies have examined reward response in CACNA1C rs1006737 risk allele carriers. Lancaster et al. (2014) found that CACNA1C risk allele carriers had a blunted behavioural response in a reward‐based task compared to non‐carriers (Lancaster et al. 2014). Wessa et al. (2010) tested reward reversal learning and reported increased amygdala activity in CACNA1C rs1006737 risk allele carriers in response to delivery of reward (Wessa et al. 2010). Using conditional cacna1c knockout mice in the behavioural sensitization protocol, we have found that Cav1.2 channels in the NAc mediate the long‐term expression of the sensitized response (Schierberl et al. 2011 a). Using the CPP protocol we find that constitutive heterozygous cacna1c mice have a potentiated cocaine reward response (Schierberl et al. 2011 b). Ongoing studies are currently examining the neural circuitry and molecular mechanisms that underlie the enhanced reward response in constitutive heterozygous cacna1c mice.

CACNA1D

A new study from our group has identified CACNA1D SNPs in cocaine dependent individuals. Examination of 947 CACNA1D SNPs has identified three significant SNPs associated with cocaine dependence (Martinez‐Rivera et al. 2015). To date, this is the only human genetic study that has been reported in a cocaine‐dependent population.

Using cacna1d knockout mice and Cav1.2 DHP‐insensitive mutant mice (Sinnegger‐Brauns et al. 2004), we have demonstrated a role for Cav1.3 channels in the VTA in the development of behavioural sensitization (Schierberl et al. 2011 a), in mediating dopamine D2 receptor‐induced molecular changes in the striatum (Schierberl et al. 2012) and in the acquisition of cocaine CPP (Martinez‐Rivera et al. 2015). A new study supporting our data finds that the LTCC blocker isradipine, injected directly into the rat VTA, blocks acquisition of cocaine CPP (potentially via Cav1.3 channels as Cav1.3 is the predominant subunit expressed in VTA neurons; Rajadhyaksha et al. 2004). They further extend these findings to demonstrate that isradipine can enhance extinction of cocaine CPP and block cocaine‐induced reinstatement (Degoulet et al. 2016), a model of relapse to drug taking behaviour. Similarly, the LTCC blockers nifedipine and isradipine, infused into the VTA, attenuate cue‐induced cocaine seeking in the rat cocaine self‐administration model (Nunes et al. 2015). Based on our human genetic findings and a role for cacna1d in addictive behaviour in rodents, additional studies to explore CACNA1D in mood disorders is warranted.

Conclusion

Several recent human genetic studies have identified L‐type Ca2+ channel genes CACNA1C and CACNA1D as candidate risk genes in neuropsychiatric and neurodevelopmental disorders. Human neuroimaging studies, along with cellular and mouse studies, have established an important role for Cav1.2 and Cav1.3 channels, encoded by cacna1c and cacna1d, respectively, in intermediate phenotypes relevant to neuropsychiatric disorders. In this review we have integrated human behavioural and neuroimaging data with neuropsychiatric‐related behavioural domains and endophenotypes, to allow a platform to pose experimental questions towards gaining a better understanding of neural mechanisms that underlie neuropsychiatric disorders in which CACNA1C and CACNA1D have been implicated. Within this framework, the time is ideal to exploit the newly developed genetic, cellular and molecular tools for neuroscience research to move forward in our understanding of the impact of the newly discovered CACNA1C and CACNA1D human polymorphisms on the brain and behaviour.

Additional information

Competing interests

None declared.

Funding

The authors’ work is supported by the National Institute of Drug Abuse (NIDA)/National Institute of Health (NIH) 5R01DA029122(A.M.R.), NIDA/NIH F31 DA032169‐01A1 (A.S.L.), The Hartwell Foundation (A.M.R.) and the Weill Cornell Autism Research Program (A.M.R.).

Biographies

Zeeba Kabir is a postdoctoral fellow in the Rajadhyaksha Lab. Her interest is in the role of Cav1.2 and Cav1.3 L‐type Ca2+ channels in cognition and understanding the underlying anatomical and molecular processes.

graphic file with name TJP-594-5823-g001.gif

Anni Lee recently completed her PhD in the Rajadhyaksha Lab. Her work has contributed to describing the role of the neuronal Cav1.2 L‐type Ca2+ channel and its downstream molecules in anxiety, depression and addictive behaviours.

Anjali Rajadhyaksha is a molecular neuroscientist with scientific interest in understanding the contribution of Cav1.2 and Cav1.3 L‐type Ca2+ channel mechanisms to behaviours related to neuropsychiatric disorders including addiction and mood disorders. The group's research methods include the use of genetically modified mouse models, stereotaxic techniques to generate site‐ and cell‐type‐specific knockouts coupled with biochemical studies and rodent behavioural tests that encompass a range of human neuropsychiatric‐related phenotypes to better understand the molecular mechanisms underlying brain disorders in the context of behavioural deficits.

This review was presented at the symposium “Voltage‐gated calcium channels ‐ from basic mechanisms to disease”, which took place at Physiology 2015 in Cardiff, UK, 6–8 July 2015.

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