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

Abstract

Schizophrenia shows high heritability and several of the genes associated with this disorder are involved in calcium (Ca2+) 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 Ca2+ 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.

Variant-to-gene mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as a regulator of sleep

“…Despite the ability for high-throughput behavioral screening, unexpectedly few studies have used these models to validate genes identified in human GWAS studies. In fruit flies, the voltage-gated Ca 2+ channel cacophony ( 61 ) and the adenosine triphosphate–sensitive potassium channel, ABCC9 ( 62 ), have been identified as sleep regulators following their identification in human GWAS. In addition, cross-species analysis has found that the epidermal growth factor receptor promotes sleep in C. elegans , Drosophila , and zebrafish and is associated with variation in human sleep duration and quality ( 63 – 65 ).…”

DYRK1a Inhibitor Mediated Rescue of Drosophila Models of Alzheimer’s Disease-Down Syndrome Phenotypes

“…Olfactory memory experiments were performed as previously described ( Malik et al, 2013 ; Hidalgo et al, 2021a ; Hidalgo et al, 2021b ). Groups of 20–40 (mixed sex) flies were collected about 2–5 days prior to testing and kept under LD 25°C and 70% relative humidity conditions to acclimatise to the environment they would be tested in.…”

Lipophorin receptors regulate mushroom body development and complex behaviors in Drosophila

“…The process consists of airflow passing through bubbling mineral oil or a solution of the odorant dissolved in mineral oil. The experiments were conducted under dim red light to prevent confounding visual effects on olfactory memory formation [ 99 , 100 ].…”