Sex-specific effects of Cacna1c haploinsufficiency on object recognition, spatial memory, and reversal learning capabilities in rats

Braun, Moria D.; Kisko, Theresa M.; Vecchia, Débora Dalla; Andreatini, Roberto; Schwarting, Rainer K.W.; Wöhr, Markus

doi:10.1016/j.nlm.2018.05.012

Cited by 18 publications

(16 citation statements)

References 55 publications

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“…12,39,40 Moreover, the role of Cacna1c in regulating relevant behavioral phenotypes during the critical developmental period of adolescence, which is characterized by a particularly rich social behavior repertoire including social play behavior, [47][48][49] has not been extensively studied. In light of the evidence for sex-dependent effects in rodents 12,81,82 and humans, 12,39,40 and our previous report on reduced pro-social 50-kHz USV during rough-and-tumble play behavior in male Cacna1c haploinsufficient rats, 45 the rewarding nature of social play, 63 this would suggest that playful encounters were equally rewarding for Cacna1c +/− females as they were for Cacna1c +/+ littermate controls. However, the substantial increase in pinning in Cacna1c +/− females speaks against equivalent reward levels between the two genotypes.…”

Section: Discussionmentioning

confidence: 93%

“…69 Due to the sex-dependent influences of SNPs within CACNA1C on diagnosis, course, and recovery in humans, 12,39,40 we reasoned that a sex-specific assessment of social behavior and communication with relevance to neuropsychiatric disorders in Cacna1c haploinsufficient rats might provide novel insights into the complex role CACNA1C appears to play. 82 To our knowledge, sexspecific effects of Cacna1c haploinsufficiency in the context of social behavior and communication have not yet been studied in relevant rodent models. Specifically, Cacna1c haploinsufficiency in mice was reported to result in increased anxiety-related behavior, decrease development of learned helplessness, decreased startle responsivity, and greater attenuation of amphetamine-induced hyperlocomotion in females than in males.…”

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confidence: 99%

“…12 Moreover, evidence for a sex-dependent modulation of age-related cognitive decline was obtained in mice 81 and we recently found sex-specific effects of Cacna1c haploinsufficiency on spatial memory and reversal learning in rats. 82 To our knowledge, sexspecific effects of Cacna1c haploinsufficiency in the context of social behavior and communication have not yet been studied in relevant rodent models.…”

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confidence: 99%

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Sex‐dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats

Kisko

Braun

Michels

et al. 2019

Genes Brain and Behavior

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As cross‐disorder risk gene, CACNA1C is implicated in the etiology of all major neuropsychiatric disorders characterized by deficits in social behavior and communication and there is evidence for sex‐dependent influences of single‐nucleotide polymorphisms within CACNA1C on diagnosis, course, and recovery in humans. In this study, we aimed, therefore, at further exploring the role of Cacna1c in regulating behavioral phenotypes, focusing on sex‐specific differences in social behavior and communication during the critical developmental period of adolescence in rats. Specifically, we compared rough‐and‐tumble play, concomitant emission of pro‐social 50‐kHz ultrasonic vocalizations, and social approach behavior in response to playback of 50‐kHz ultrasonic vocalizations between constitutive heterozygous Cacna1c +/− females and wildtype Cacna1c +/+ littermate controls, and contrasted present female findings to data previously reported in males. Our results show for the first time that partial depletion of Cacna1c leads to sex‐dependent alterations in social behavior and communication in rats. In females, Cacna1c haploinsufficiency led to hypermasculinization, with rough‐and‐tumble play behavior, in general, and pinning behavior, in particular, being even higher than in males without affecting concomitant 50‐kHz ultrasonic vocalizations. In males, in contrast, rough‐and‐tumble play behavior was not altered, yet emission of 50‐kHz ultrasonic vocalizations was diminished following partial Cacna1c depletion. The behavioral responses elicited by playback of 50‐kHz ultrasonic vocalizations were reduced upon partial Cacna1c depletion in both sexes. It thus can be concluded that Cacna1c plays a prominent sex‐dependent role in regulating juvenile rat social play behavior and pro‐social 50‐kHz ultrasonic communication with relevance to sex‐specific effects seen in neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 93%

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confidence: 99%

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Sex‐dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats

Kisko

Braun

Michels

et al. 2019

Genes Brain and Behavior

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“…Seizures were inhibited by ethosuximide and valproic acid but not phenytoin in Cacna1a-mutant GRY rat for absence seizures [ 143 ]. Acetazolamide could abolish stress-induced ataxia in mice [ 144 ] Apoptotic pathway in ataxia [ 152 ] CACNA1C Calcium voltage-gated channel subunit alpha1 C Cav1.2 L-type Genetic Cacna1c rat model [ 239 ]. Cacna1c knockout model [ 240 ].…”

Section: Resultsmentioning

confidence: 99%

Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

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“…Transgenic rodent models demonstrate some behavioral defects that parallel humans with CACNA1C SNPs (Bhat et al, 2012;Kabir et al, 2016). With respect to "autism-like" behaviors, CACNA1C heterozygous mice show mild defects in social behavior but very few changes in exploratory, anxiety-like, and learning behaviors (Kabitzke et al, 2018) while CACNA1C haploinsufficient rats do display mild defects in prosocial vocalizations without other overt behavioral phenotypes and even mild improvements in spatial memory function (Braun et al, 2018;Kisko et al, 2018;Michels et al, 2019). Haploinsufficient CACNA1C mice demonstrated reduced anxiety, reduced locomotion in the amphetamine-induced hyperactivity model of psychosis, and reduced depressive-like behavioral phenotypes (Dao et al, 2010).…”

Section: Neuropsychiatric Disordersmentioning

confidence: 99%

Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

Hopp

2020

J of Neuroscience Research

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Calcium (Ca2+) is a ubiquitous mediator of a multitude of cellular functions in the central nervous system (CNS). Intracellular Ca2+ is tightly regulated by cells, including entry via plasma membrane Ca2+ permeable channels. Of specific interest for this review are L‐type voltage‐dependent Ca2+ channels (L‐VDCCs), due to their pleiotropic role in several CNS disorders. Currently, there are numerous approved drugs that target L‐VDCCs, including dihydropyridines. These drugs are safe and effective for the treatment of humans with cardiovascular disease and may also confer neuroprotection. Here, we review the potential of L‐VDCCs as a target for the treatment of CNS disorders with a focus on microglia L‐VDCCs. Microglia, the resident immune cells of the brain, have attracted recent attention for their emerging inflammatory role in several CNS diseases. Intracellular Ca2+ regulates microglia transition from a resting quiescent state to an “activated” immune‐effector state and is thus a valuable target for manipulation of microglia phenotype. We will review the literature on L‐VDCC expression and function in the CNS and on microglia in vitro and in vivo and explore the therapeutic landscape of L‐VDCC‐targeting agents at present and future challenges in the context of Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropsychiatric diseases, and other CNS disorders.

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Sex-specific effects of Cacna1c haploinsufficiency on object recognition, spatial memory, and reversal learning capabilities in rats

Cited by 18 publications

References 55 publications

Sex‐dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats

Sex‐dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats

Calcium channelopathies and intellectual disability: a systematic review

Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

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