Molecular Autism最新文献

Background: The MECP2 gene is located on the X chromosome and encodes a methyl-CpG-binding protein 2 involved in transcriptional regulation. Loss-of-function mutations in the MECP2 gene lead to Rett syndrome, a severe neurodevelopmental disorder. The clinical picture of Rett syndrome includes, among other symptoms, social deficits, learning impairment, and heightened anxiety. The amygdala is a brain region responsible for emotional learning and is involved in the regulation of social behaviour as well as fear and anxiety. Parvalbumin interneurons tightly control the excitability, oscillation and synchronisation of the amygdala network, which are relevant to its functions. Here, we investigated the effects of Mecp2 gene ablation in parvalbumin interneurons on the microcircuit and functional connectivity of the mouse amygdala.

Methods: Male mice with conditional knockout of the Mecp2 gene in parvalbumin interneurons were used as a genetic mouse model. Littermates with an intact gene were used as controls. Ex vivo brain slice electrophysiology, combined with pharmacology and optogenetics, was utilised to characterise microcircuits within the lateral amygdala. In vivo functional ultrasound imaging was used to visualise the connectivity within the amygdala-ventral hippocampus-prefrontal cortex network triad.

Results: Loss of Mecp2 in parvalbumin interneurons significantly attenuated GABAergic synaptic input to principal neurons in the lateral amygdala. The deficit in inhibition was accompanied by higher excitability of local principal neurons in adult animals. A deficient in vivo functional connectivity of the amygdala with the ventral hippocampus and prefrontal cortex was observed in conditional knockouts.

Limitations: This study used only male mice. Mecp2 knockout males exhibit shorter latency to symptom onset and lower phenotypic variability, making them suitable for mechanistic studies. Since previous studies in the field used males, we aimed to advance the existing body of research using the same approach. Finally, the link between the effects observed and possible behavioural alterations needs further investigation.

Conclusions: Our study characterised the consequences of Mecp2 loss in parvalbumin interneurons on amygdala microcircuit function and connectivity within the prefrontal cortex‒amygdala‒hippocampus triad. It also provided evidence that supports and complements previous findings on the role of interneurons in the functional deficits observed in Mecp2 knockout animal models.

Background: The etiology of severe childhood speech disorders, including childhood apraxia of speech (CAS), is currently understood as genetically heterogeneous, with over 40 distinct monogenic conditions reported to date. Among them, the p.Thr327Arg variant in GNAO1, encoding the major neuronal G protein Gαo, was identified in one patient diagnosed with CAS and intellectual disability (ID). This presentation is exceptionally rare, as GNAO1 mutations are commonly associated with epilepsy, hyperkinetic movement disorders, and global developmental delay, often accompanied by ID.

Methods: Here, we describe the clinical course of two patients with de novo heterozygous GNAO1 variants-p.Leu39_Gly40insVal and p.Thr327Lys-who exhibit severe speech disorder and ID as prominent symptoms. We also analyzed the biochemical and cellular properties of the mutant Gαo proteins alongside the previously reported p.Thr327Arg variant.

Results: Molecular investigation of these three atypical Gαo mutants revealed aberrant GTP binding and hydrolysis, impaired association with RGS19, and a strong neomorphic gain of Ric8A interaction. Yet, all variants show normal plasma membrane localization despite poor Gβγ association, with p.Leu39_Gly40insVal exhibiting weak coupling to G protein-coupled receptors and p.Thr327Arg/Lys displaying near-normal coupling. Importantly, all three Gαo variants respond to Zn²⁺, supporting the potential therapeutic use of zinc supplementation for the patients.

Limitations: These rare findings are based on a limited number of cases and require confirmation in additional patients to establish firmer genotype-phenotype correlations for GNAO1-related severe speech disorders.

Conclusions: Our results broaden the clinical and mechanistic spectrum of GNAO1-related disorders, showing that severe speech disorders and ID can occur as defining features even in the absence of seizures or movement disorders. These findings highlight the importance of including GNAO1 in genetic testing for children with severe speech disorders.