PT - JOURNAL ARTICLE AU - Radhika S Joshi AU - Mitradas M. Panicker TI - Identifying the <em>in Vivo</em> Cellular Correlates of Antipsychotic Drugs AID - 10.1523/ENEURO.0220-18.2018 DP - 2018 Oct 08 TA - eneuro PG - ENEURO.0220-18.2018 4099 - http://www.eneuro.org/content/early/2018/10/08/ENEURO.0220-18.2018.short 4100 - http://www.eneuro.org/content/early/2018/10/08/ENEURO.0220-18.2018.full AB - GPCRs such as 5-HT2A and D2 are implicated in the therapeutic and the side effects of antipsychotics. However, the pattern of brain activity that leads to the behavioural effects of antipsychotics is poorly understood. To address this question, we used the transgenic ‘FosTRAP’ mice (Mus musculus), where a fluorescent reporter marks the cells responsive to the stimulus of interest. Here the stimulus was an administration of various antipsychotic drugs. In case of typical antipsychotics such as Haloperidol, the c-fos active cells were predominantly found in the striatum whereas in case of the atypical antipsychotics (Clozapine and Olanzapine) c-fos induced cells were more numerous in the cortical regions e.g., orbital cortex, piriform cortex. Curiously, we also observed ependymal cells to be a novel cellular target of atypical antipsychotics. 5-HT2A is considered to be a major target for atypical antipsychotics. Therefore, we bred ‘FosTRAP’ mice with 5-HT2A knockout mice and tested their response to the prototype of atypical antipsychotics- Clozapine. Interestingly, the absence of 5-HT2A did not significantly affect the number of c-fos induced cells in the cortical regions. However, the ependymal cells showed a dramatically reduced response to Clozapine in the absence of 5-HT2A. In summary, the TRAP system has allowed us to identify various region-specific activity induced by antipsychotics and novel cellular targets of the antipsychotics. These results serve as a ‘proof of principle’ study that can be extended to explore the biochemical and physiological changes brought about by antipsychotics and specifically identify antipsychotic-responsive cells in the live tissue.Significance Statement Antipsychotic drugs have been the first choice of treatment for mental illnesses such as Schizophrenia. Thorough understanding of the cellular and neuronal targets of these drugs should deepen our understanding of the pathophysiology of the mental disorders and help the development of improved therapy. We report here the use of FosTrap mice that allowed us to label cells and brain areas that were responsive to the antipsychotic treatment. We identified brain regions such as orbital cortex, piriform cortex and ventral posteromedial thalamus as the targets of the atypical class of antipsychotics. Importantly, we also report for the first time that, ependymal cells, lining the ventricles, are targeted by the atypical antipsychotics and this effect is modulated by the 5-HT2A receptor.