The behavioral and neurochemical characterization of a Drosophila dysbindin mutant supports the contribution of serotonin to schizophrenia negative symptoms

Hidalgo, Sergio; Castro, Christian; Zárate, Rafaella V.; Valderrama, Benjamín; Hodge, James J L; Campusano, Jorge M.

doi:10.1016/j.neuint.2020.104753

Cited by 10 publications

(17 citation statements)

References 83 publications

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“…Further studies should be conducted to explore whether similar phenotypes are observed with other schizophrenia-associated genes in Drosophila . We have recently described that the Drosophila dysb 1 mutant displays similar olfactory and social deficits as the ones here described for Rim 57 , further supporting the use of Drosophila mutants to test schizophrenia pathophysiology. In addition, new drug treatments could be tested in this model, for instance, to compare their efficiency with currently available treatments.…”

Section: Discussionsupporting

confidence: 74%

“…After 2 h of acclimatization in the room where the experiment would take place, flies were loaded into the social space arena, consisting in an isosceles triangle with base of 14.5 cm and height of 14.8 cm, giving a free space area of about 86.5 cm 2 . The arena was homemade out of glass and acrylic as previously reported 56 , 57 . A period of 30 min was given to allow the flies to assume static positions within the arena 56 .…”

Section: Methodsmentioning

confidence: 99%

“…A period of 30 min was given to allow the flies to assume static positions within the arena 56 . Afterwards, a single photo was taken and the distance of each fly to its nearest neighbour was calculated using Fiji software 56 , 57 .…”

Section: Methodsmentioning

confidence: 99%

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

2021

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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.

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Section: Discussionsupporting

confidence: 74%

Section: Methodsmentioning

confidence: 99%

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

2021

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“…In addition, a recent work from our group showed deficits in social behavior and locomotion in a Drosophila mutant for the dysbindin gene, an animal model for schizophrenia. Interestingly, the phenotypes observed in the dysbindin mutants seem to depend at least in part on altered serotonergic signaling (Hidalgo et al, 2020).…”

Section: Drosophila As An Animal Model For Studying the Contribution Of Serotonin To Neurodevelopmental And Mental Disorders?mentioning

confidence: 99%

Studying the Contribution of Serotonin to Neurodevelopmental Disorders. Can This Fly?

Carvajal-Oliveros

Campusano

2021

Front. Behav. Neurosci.

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Serotonin is a biogenic amine that acts as neurotransmitter in different brain regions and is involved in complex behaviors, such as aggression or mood regulation. Thus, this amine is found in defined circuits and activates specific receptors in different target regions. Serotonin actions depend on extracellular levels of this amine, which are regulated by its synthetic enzymes and the plasma membrane transporter, SERT. Serotonin acts also as a neurotrophic signal in ontogeny and in the mature brain, controlling cell proliferation, differentiation, neurogenesis, and neural plasticity. Interestingly, early alterations in serotonergic signaling have been linked to a diversity of neurodevelopmental disorders, including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), or mental illnesses like schizophrenia or depression. It has been proposed that given the complex and numerous actions of serotonin, animal models could better serve to study the complexity of serotonin actions, while providing insights on how hindering serotonergic signaling could contribute to brain disorders. In this mini-review, it will be examined what the general properties of serotonin acting as a neurotransmitter in animals are, and furthermore, whether it is possible that Drosophila could be used to study the contribution of this amine to neurodevelopmental and mental disorders.

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“…Furthermore, genome-wide association studies also reported a link between dysbindin genetic variants and cognitive abilities including memory encoding and executive function 24,25 . These findings have led to investigations aiming at deciphering the role of BLOC1 in neuronal function 1 using not only mouse models defective for individual BLOC1 gene function but also the Drosophila model, in which the complex is well conserved 9,[26][27][28][29][30] . These studies confirmed the involvement of BLOC1 in behavior and memory.…”

Section: Introductionmentioning

confidence: 99%

Pallidin function in drosophila surface glia regulates sleep and is dependent on amino acid availability

Hui

Aboudhiaf

Parrot

et al. 2022

Preprint

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The Pallidin protein is a component of a multimeric complex named the Biogenesis of Lysosome-related Organelles Complex-1 (BLOC1) that regulates specific endosomal function and transmembrane protein trafficking in many different cell types. In the brain, defective BLOC1 function has been linked to schizophrenia, a neuropsychiatric disorder with highly prevalent sleep disruptions, and to impaired cognitive abilities in healthy subjects. In animal models, defective BLOC-1 function also impairs behavior, memory, neurotransmission systems and metabolism. This growing body of experimental evidence suggest an involvement of BLOC1 in sleep/wake regulation. Here, we used Drosophila molecular genetics and conditional, cell-type specific knockdown strategy to address this question. We show that down-regulation of a central subunit of BLOC1, Pallidin, in the surface glia, the Drosophila equivalent of the blood brain barrier, is sufficient to reduce, fragment and delay nighttime sleep at the adult stage and in a circadian clock dependent manner. Other members of the BLOC1 complex appear to be involved in this surface glia-dependent sleep regulation. In agreement with a BLOC1 involvement in amino acid transport, down-regulation of the Large neutral Amino acid Transporter 1 (LAT1)-like transporters JhI-21 and minidiscs, phenocopy the down-regulation of pallidin. Similar results were obtained by inhibiting the TOR amino acid signaling pathway. Supplementing food with essential amino acids normalizes the sleep/wake phenotypes of pallidin and JhI-21 down-regulation. Furthermore, we identify a role for pallidin in the subcellular trafficking of JhI-21 in surface glial cells. Finally, we provide evidence that Pallidin function in surface glia is required for GABAergic neurons activation involved in promoting sleep. Taken together, these data identify a novel role for BLOC1 that, through LAT1-like transporters subcellular trafficking modulates essential amino acid availability and GABAergic sleep/wake regulation.

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The behavioral and neurochemical characterization of a Drosophila dysbindin mutant supports the contribution of serotonin to schizophrenia negative symptoms

Cited by 10 publications

References 83 publications

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

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

Studying the Contribution of Serotonin to Neurodevelopmental Disorders. Can This Fly?

Pallidin function in drosophila surface glia regulates sleep and is dependent on amino acid availability

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