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Schizophrenia shows high heritability and several of the genes associated with this disorder are involved in calcium (Ca 2+ ) signalling and synaptic function. One of these is the  Rab-3 interacting molecule-1  ( RIM1 ), which has recently been associated with schizophrenia by Genome Wide Association Studies (GWAS). However, its contribution to the pathophysiology of this disorder remains unexplored. In this work, we use  Drosophila  mutants of the orthologue of  RIM1 ,  Rim , to model some aspects of the classical and non-classical symptoms of schizophrenia.  Rim  mutants showed several behavioural features relevant to schizophrenia including social distancing and altered olfactory processing. These defects were accompanied by reduced evoked Ca 2+  influx and structural changes in the presynaptic terminals sent by the primary olfactory neurons to higher processing centres. In contrast, expression of  Rim-RNAi  in the mushroom bodies (MBs), the main memory centre in flies, spared learning and memory suggesting a differential role of Rim in different synapses. Circadian deficits have been reported in schizophrenia. We observed circadian locomotor activity deficits in  Rim  mutants, revealing a role of Rim in the pacemaker ventral lateral clock neurons (LNvs). These changes were accompanied by impaired day/night remodelling of dorsal terminal synapses from a subpopulation of LNvs and impaired day/night release of the circadian neuropeptide pigment dispersing factor (PDF) from these terminals. Lastly, treatment with the commonly used antipsychotic haloperidol rescued  Rim  locomotor deficits to wildtype. This work characterises the role of Rim in synaptic functions underlying behaviours disrupted in schizophrenia.

Assessing olfactory, memory, social and circadian phenotypes associated with schizophrenia in a genetic model based on Rim