PMID- 30304534
OWN - NLM
STAT- MEDLINE
DCOM- 20200710
LR  - 20220129
IS  - 1745-1701 (Electronic)
IS  - 0586-7614 (Print)
IS  - 0586-7614 (Linking)
VI  - 45
IP  - 5
DP  - 2019 Sep 11
TI  - Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal 
      Learning Across Species.
PG  - 1024-1032
LID - 10.1093/schbul/sby146 [doi]
AB  - Genetic variation in CACNA1C, which encodes the alpha-1 subunit of Cav1.2 L-type 
      voltage-gated calcium channels (VGCCs), has been strongly linked to risk for 
      psychiatric disorders including schizophrenia and bipolar disorder. How genetic 
      variation in CACNA1C contributes to risk for these disorders is however not fully 
      known. Both schizophrenia and bipolar disorder are associated with impairments in 
      reversal learning (RL), which may contribute to symptoms seen in these 
      conditions. We used a translational RL paradigm to investigate whether genetic 
      variation in CACNA1C affects RL in both humans and transgenic rats. Associated 
      changes in gene expression were explored using in situ hybridization and 
      quantitative PCR in rats and the BRAINEAC online human database. Risk-associated 
      genetic variation in CACNA1C in healthy human participants was associated with 
      impairments in RL. Consistent with this finding, rats bearing a heterozygous 
      deletion of Cacna1c were impaired in an analogous touchscreen RL task. We 
      investigated the possible molecular mechanism underlying this impairment and 
      found that Cacna1c +/- rats show decreased expression of Bdnf in prefrontal 
      cortex. Examination of BRAINEAC data showed that human risk-associated genetic 
      variation in CACNA1C is also associated with altered expression of brain-derived 
      neurotrophic factor (BDNF) in the prefrontal cortex in humans. These results 
      indicate that genetic variation in CACNA1C may contribute to risk for 
      schizophrenia and bipolar disorder by impacting behavioral flexibility, 
      potentially through altered regulation of BDNF expression in the prefrontal 
      cortex. Tests of RL may be useful for translational studies and in the 
      development of therapies targeting VGCCs.
CI  - (c) The Author(s) 2018. Published by Oxford University Press on behalf of the 
      Maryland Psychiatric Research Center.
FAU - Sykes, Lucy
AU  - Sykes L
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
FAU - Haddon, Josephine
AU  - Haddon J
AD  - School of Psychology, Cardiff University, Cardiff, UK.
FAU - Lancaster, Thomas M
AU  - Lancaster TM
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
AD  - School of Psychology, Cardiff University, Cardiff, UK.
FAU - Sykes, Arabella
AU  - Sykes A
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
FAU - Azzouni, Karima
AU  - Azzouni K
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
FAU - Ihssen, Niklas
AU  - Ihssen N
AD  - Department of Psychology, Durham University, Durham, UK.
FAU - Moon, Anna L
AU  - Moon AL
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
AD  - School of Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, 
      Cardiff University, Cardiff, UK.
FAU - Lin, Tzu-Ching E
AU  - Lin TE
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
FAU - Linden, David E
AU  - Linden DE
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
AD  - School of Psychology, Cardiff University, Cardiff, UK.
AD  - School of Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, 
      Cardiff University, Cardiff, UK.
FAU - Owen, Michael J
AU  - Owen MJ
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
AD  - School of Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, 
      Cardiff University, Cardiff, UK.
FAU - O'Donovan, Michael C
AU  - O'Donovan MC
AD  - School of Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, 
      Cardiff University, Cardiff, UK.
FAU - Humby, Trevor
AU  - Humby T
AD  - School of Psychology, Cardiff University, Cardiff, UK.
FAU - Wilkinson, Lawrence S
AU  - Wilkinson LS
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
AD  - School of Psychology, Cardiff University, Cardiff, UK.
AD  - School of Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, 
      Cardiff University, Cardiff, UK.
FAU - Thomas, Kerrie L
AU  - Thomas KL
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
AD  - School of Biosciences, Cardiff University, Cardiff, UK.
FAU - Hall, Jeremy
AU  - Hall J
AD  - Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, 
      UK.
AD  - School of Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, 
      Cardiff University, Cardiff, UK.
LA  - eng
GR  - MR/L010305/1/MRC_/Medical Research Council/United Kingdom
GR  - 100202/Z/12/Z/WT_/Wellcome Trust/United Kingdom
GR  - MR/P005748/1/MRC_/Medical Research Council/United Kingdom
GR  - Wellcome Trust/United Kingdom
GR  - MR/R011397/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Schizophr Bull
JT  - Schizophrenia bulletin
JID - 0236760
RN  - 0 (Bdnf protein, rat)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (CACNA1C protein, human)
RN  - 0 (Cacna1c protein, rat)
RN  - 0 (Calcium Channels, L-Type)
RN  - 7171WSG8A2 (BDNF protein, human)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Bipolar Disorder/genetics
MH  - Brain-Derived Neurotrophic Factor/genetics/metabolism
MH  - Calcium Channels, L-Type/*genetics
MH  - Databases, Genetic
MH  - Female
MH  - Gene Expression
MH  - Gene Expression Regulation
MH  - Gene Knockout Techniques
MH  - Genetic Variation
MH  - Genotype
MH  - Healthy Volunteers
MH  - Heterozygote
MH  - Humans
MH  - In Situ Hybridization
MH  - Male
MH  - Middle Aged
MH  - Polymerase Chain Reaction
MH  - Prefrontal Cortex/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reversal Learning/*physiology
MH  - Schizophrenia/genetics
MH  - Young Adult
PMC - PMC6737471
OTO - NOTNLM
OT  - BDNF
OT  - behavior
OT  - calcium
OT  - rat
OT  - reversal learning
OT  - translational
EDAT- 2018/10/12 06:00
MHDA- 2020/07/11 06:00
PMCR- 2018/10/10
CRDT- 2018/10/11 06:00
PHST- 2018/10/12 06:00 [pubmed]
PHST- 2020/07/11 06:00 [medline]
PHST- 2018/10/11 06:00 [entrez]
PHST- 2018/10/10 00:00 [pmc-release]
AID - 5126371 [pii]
AID - sby146 [pii]
AID - 10.1093/schbul/sby146 [doi]
PST - ppublish
SO  - Schizophr Bull. 2019 Sep 11;45(5):1024-1032. doi: 10.1093/schbul/sby146.