Abstract
Recent advances in the genetics of neurodevelopmental disorders (NDDs) have identified the transcription factor FOXP2 as one of numerous risk genes, e.g. in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). FOXP2 function is suggested to be involved in GABAergic signalling and numerous studies demonstrate that GABAergic function is altered in NDDs, thus disrupting the excitation/inhibition balance. Interestingly, GABAergic signalling components, including glutamate-decarboxylase 1 (Gad1) and GABA receptors, are putative transcriptional targets of FOXP2. However, the specific role of FOXP2 in the pathomechanism of NDDs remains elusive. Here we test the hypothesis that Foxp2 affects behavioural dimensions via GABAergic signalling using zebrafish as model organism. We demonstrate that foxp2 is expressed by a subset of GABAergic neurons located in brain regions involved in motor functions, including the subpallium, posterior tuberculum, thalamus and medulla oblongata. Using CRISPR/Cas9 gene-editing we generated a novel foxp2 zebrafish loss-of-function mutant that exhibits increased locomotor activity. Further, genetic and/or pharmacological disruption of Gad1 or GABA-A receptors causes increased locomotor activity, resembling the phenotype of foxp2 mutants. Application of muscimol, a GABA-A receptor agonist, rescues the hyperactive phenotype induced by the foxp2 loss-of-function. By reverse translation of the therapeutic effect on hyperactive behaviour exerted by methylphenidate, we note that application of methylphenidate evokes different responses in wildtype compared to foxp2 or gad1b loss-of-function animals. Together, our findings support the hypothesis that foxp2 regulates locomotor activity via GABAergic signalling. This provides one targetable mechanism, which may contribute to behavioural phenotypes commonly observed in NDDs.
Highlights
Ever larger and improved genetic studies have enabled substantial progress in the discovery of risk genes for neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD)
We found that gad1b knock-down Here we explore the hypothesis that Foxp2 and GABAergic induces a hyperactive phenotype similar to that of foxp2 mutants signalling are part of a biological network involved in the (Fig. 4D)
We show that foxp2 loss-ofwildtype individuals, with a stronger effect and in function results in increased locomotor activity and demonstrate absence of any developmental delay or anatomical alterations that foxp2 is expressed by GABAergic neurons in several brain through the acute application of the Gad antagonist L-allylglycine regions involved in motor functions
Summary
Ever larger and improved genetic studies have enabled substantial progress in the discovery of risk genes for neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). Apart from humans, Foxp2/foxp expression has been described for additional mammalian species as well as for birds, reptiles, amphibians and fish, including zebrafish (Danio rerio) [7,8,9,10,11,12,13,14,15,16,17] These studies revealed a highly concordant localisation within the CNS, which coincides with regions involved in motor functions and suggest a functional conservation of Foxp. A gad1b loss-of-function was created by injections of a splice-inhibiting ranging from myelination to synaptic communications [36, 37] These mechanisms program the maturation of interneurons, e.g. MSN, allowing strong GABA-mediated feed-forward inhibimorpholino oligonucleotide (GeneTools, Table S1) into the animal pole of fertilised one-cell stage eggs. Swimming tracks were recorded in the dark with an infrared backlight with a
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