Schizophrenia exhibits up to 80% heritability. A number of genome wide association studies (GWAS) have shown voltage-gated calcium (Cav) channel genes such as CACNA1A (Cav2.1 P/Q-type) and CACNA1B (Cav2.2 N-type) containing common variants that contribute to the risk for the disease. Furthermore, studies using whole exome sequencing have also found that CACNA1B deletions and rare disruptive variants in CACNA1A are associated with schizophrenia. The negative symptoms of schizophrenia include behavioural defects such as impaired memory, sleep and circadian rhythms. It is not known how variants in schizophrenia-associated genes contribute to cognitive and behavioural symptoms, thus hampering the development of treatment for schizophrenia symptoms. In order to address this knowledge gap, we studied behavioural phenotypes in a number of loss of function mutants for the Drosophila ortholog of the Cav2 gene family called cacophony (cac). cac mutants showed several behavioural features including decreased night-time sleep and hyperactivity similar to those reported in human patients. The change in timing of sleep-wake cycles suggested disrupted circadian rhythms, with the loss of night-time sleep being caused by loss of cac just in the circadian clock neurons. These animals also showed a reduction in rhythmic circadian behaviour a phenotype that also could be mapped to the central clock. Furthermore reduction of cac just in the clock resulted in a lengthening of the 24h period. In order to understand how loss of Cav2 function may lead to cognitive deficits and underlying cellular pathophysiology we targeted loss of function of cac to the memory centre of the fly, called the mushroom bodies (MB). This manipulation was sufficient to cause reduction in both short- and intermediate-term associative memory. Memory impairment was accompanied by a decrease in Ca2+ transients in response to a depolarizing stimulus, imaged in the MB presynaptic terminals. This work shows loss of cac Cav2 channel function alone causes a number of cognitive and behavioural deficits and underlying reduced neuronal Ca2+ transients, establishing Drosophila as a high-throughput in vivo genetic model to study the Cav channel pathophysiology related to schizophrenia.
Bibliographical noteFunding Information:
The authors would like to thank Drs Scott Waddell, Ralf Stanewsky and the Bloomington Drosophila Stock Center for sending fly stocks. This work was supported by PUC-VRI Puente Grants No. P-1805 to J.M.C. S.H. was supported by CONICYT-PCHA/Doctorado Nacional/2016-21161611 and J.J.L.H. by a Leverhulme Trust grant (RPG-2016-318).
The authors would like to thank Drs Scott Waddell, Ralf Stanewsky and the Bloomington Drosophila Stock Center for sending fly stocks. This work was supported by PUC -VRI Puente Grants No. P-1805 to J.M.C. S.H. was supported by CONICYT -PCHA/Doctorado Nacional/ 2016-21161611 and J.J.L.H. by a Leverhulme Trust grant ( RPG-2016-318 ).
© 2021 The Authors
- voltage-gated calcium channel
- circadian rhythms
- calcium imaging