Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits

Kanellopoulos, Alexandros K.; Mariano, Vittoria; Spinazzi, Marco; Woo, Young Woon; McLean, Colin; Pech, Ulrike; Li, Ka Wan; Armstrong, J. D.; Giangrande, Angela; Callaerts, Patrick; Smit, August B.; Abrahams, Brett S.; Fiala, André; Achsel, Tilmann; Bagni, Claudia

doi:10.1016/j.cell.2020.02.044

Cited by 80 publications

(69 citation statements)

References 174 publications

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“…Our observations of reduced number, but normal volume, of presynaptic mitochondria in Cyfip2 +/− neurons contradict the results of a recent report showing increased mitochondrial activity and size in Drosophila Cyfip mutants [13]. Only one Cyfip gene exists in Drosophila, but there are two genes, Cyfip1 and Cyfip2, in mice.…”

Section: Main Textcontrasting

confidence: 97%

Altered presynaptic function and number of mitochondria in the medial prefrontal cortex of adult Cyfip2 heterozygous mice

et al. 2020

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Variants of the cytoplasmic FMR1-interacting protein (CYFIP) gene family, CYFIP1 and CYFIP2, are associated with numerous neurodevelopmental and neuropsychiatric disorders. According to several studies, CYFIP1 regulates the development and function of both pre- and post-synapses in neurons. Furthermore, various studies have evaluated CYFIP2 functions in the postsynaptic compartment, such as regulating dendritic spine morphology; however, no study has evaluated whether and how CYFIP2 affects presynaptic functions. To address this issue, in this study, we have focused on the presynapses of layer 5 neurons of the medial prefrontal cortex (mPFC) in adult Cyfip2 heterozygous (Cyfip2+/−) mice. Electrophysiological analyses revealed an enhancement in the presynaptic short-term plasticity induced by high-frequency stimuli in Cyfip2+/− neurons compared with wild-type neurons. Since presynaptic mitochondria play an important role in buffering presynaptic Ca2+, which is directly associated with the short-term plasticity, we analyzed presynaptic mitochondria using electron microscopic images of the mPFC. Compared with wild-type mice, the number, but not the volume or cristae density, of mitochondria in both presynaptic boutons and axonal processes in the mPFC layer 5 of Cyfip2+/− mice was reduced. Consistent with an identification of mitochondrial proteins in a previously established CYFIP2 interactome, CYFIP2 was detected in a biochemically enriched mitochondrial fraction of the mouse mPFC. Collectively, these results suggest roles for CYFIP2 in regulating presynaptic functions, which may involve presynaptic mitochondrial changes.

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Section: Main Textcontrasting

confidence: 97%

Altered presynaptic function and number of mitochondria in the medial prefrontal cortex of adult Cyfip2 heterozygous mice

et al. 2020

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“…Cognitive impairment is a common feature in adults presenting with mitochondrial encephalopathy, such as MELAS (mitochondrial encephalopathy lactic acidosis, and stroke-like episodes) (8) and psychiatric symptoms are associated with MDs in up to 70% of the adult population (9,10). Along the same lines, a recent article suggested that mitochondrial activity could regulate the availability in neurons of GABA, an inhibitory neurotransmitter, leading to social deficits that can be rescued by the modulation of GABA level (11).…”

Section: Introductionmentioning

confidence: 99%

Neuropsychological and Psychiatric Features of Children and Adolescents Affected With Mitochondrial Diseases: A Systematic Review

et al. 2020

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Mitochondrial diseases (MDs) are a group of clinically heterogeneous genetic disorders that arise as the result of dysfunctional mitochondria. Only few medical articles deal with neuropsychological or psychiatric aspects of MDs. Aim: The present article aims to provide a systematic review of neuropsychological and psychiatric aspects of MDs. Methods: In order to identify all studies dealing with psychiatric and neuropsychological aspects of MDs in children and adolescents, we performed a search in the medical literature between April 2009 and April 2019 using PubMed, Cochrane, and Web of Science and we defined inclusion and exclusion criteria. Results: We found only seven studies that satisfy the inclusion requirements and criteria. The main psychiatric aspects reported in MDs were depressive and behavioral disorders. With regard to the neuropsychological aspects of MDs, developmental analyses showed an overall deterioration and developmental delay. Interpretation: Children and adolescents with MDs may present psychiatric symptoms and neuropsychological impairment. A more systematic investigation of psychiatric and neuropsychological features of MDs is needed to foster a better understanding of the phenotype of these diseases and their links with the genotype, which may have significant implications for the developmental trajectories of patients.

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“…Recently, it is reported that Aralar1 is responsible for uptake of GABA into mitochondria that is activated by mitochondrial membrane polarization. Interestingly, heterozygous aralar1 mutant flies exhibit decreased competition for food and grooming and hyperactivity, indicating a role in social activity [ 123 ]. The aralar1 gene is orthologous to the human SLC25A12 and S LC25A13 genes.…”

Section: Drosophila Epilepsy Modelsmentioning

confidence: 99%

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

Takai

Yamaguchi

Yoshida

et al. 2020

IJMS

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Developmental and epileptic encephalopathies (DEEs) are the spectrum of severe epilepsies characterized by early-onset, refractory seizures occurring in the context of developmental regression or plateauing. Early infantile epileptic encephalopathy (EIEE) is one of the earliest forms of DEE, manifesting as frequent epileptic spasms and characteristic electroencephalogram findings in early infancy. In recent years, next-generation sequencing approaches have identified a number of monogenic determinants underlying DEE. In the case of EIEE, 85 genes have been registered in Online Mendelian Inheritance in Man as causative genes. Model organisms are indispensable tools for understanding the in vivo roles of the newly identified causative genes. In this review, we first present an overview of epilepsy and its genetic etiology, especially focusing on EIEE and then briefly summarize epilepsy research using animal and patient-derived induced pluripotent stem cell (iPSC) models. The Drosophila model, which is characterized by easy gene manipulation, a short generation time, low cost and fewer ethical restrictions when designing experiments, is optimal for understanding the genetics of DEE. We therefore highlight studies with Drosophila models for EIEE and discuss the future development of their practical use.

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Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits

Cited by 80 publications

References 174 publications

Altered presynaptic function and number of mitochondria in the medial prefrontal cortex of adult Cyfip2 heterozygous mice

Altered presynaptic function and number of mitochondria in the medial prefrontal cortex of adult Cyfip2 heterozygous mice

Neuropsychological and Psychiatric Features of Children and Adolescents Affected With Mitochondrial Diseases: A Systematic Review

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

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