Dr. Ávila-Macaya, Ariel

2024, Dr. Ávila-Macaya, Ariel, Carrazana-Escalona, Ramón, Espinoza-Romero, Francisca

Vitamin A (VA) has many functions in the body, some of which are key for the development and functioning of the nervous system, while some others might indirectly influence neural function. Both hypovitaminosis and hypervitaminosis A can lead to clinical manifestations of concern for individuals and for general global health. Scientific evidence on the link between VA and autism spectrum disorder (ASD) is growing, with some clinical studies and accumulating results obtained from basic research using cellular and animal models. Remarkably, it has been shown that VA deficiency can exacerbate autistic symptomatology. In turn, VA supplementation has been shown to be able to improve autistic symptomatology in selected groups of individuals with ASD. However, it is important to recognize that ASD is a highly heterogeneous condition. Therefore, it is important to clarify how and when VA supplementation can be of benefit for affected individuals. Here we delve into the relationship between VA and ASD, discussing clinical observations and mechanistic insights obtained from research on selected autistic syndromes and laboratory models to advance in defining how the VA signaling pathway can be exploited for treatment of ASD.

2024, Dr. Ávila-Macaya, Ariel, Espinoza-Romero, Francisca, Carrazana-Escalona, Ramón, Retamal-Fredes, Eduardo, Ávila, Denisse, Papes, Fabio, Muotri, Alysson

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of transcription factor 4 (TCF4). In this work, we focused on the cerebral cortex and investigated in detail the progenitor cell dynamics and the outcome of neurogenesis in a PTHS mouse model. Labeling and quantification of progenitors and newly generated neurons at various time points during embryonic development revealed alterations affecting the dynamic of cortical progenitors since the earliest stages of cortex formation in PTHS mice. Consequently, establishment of neuronal populations and layering of the cortex were found to be altered in heterozygotes subjects at birth. Interestingly, defective layering process of pyramidal neurons was partially rescued by reintroducing TCF4 expression using focal in utero electroporation in the cerebral cortex. Coincidentally with a defective dorsal neurogenesis, we found that ventral generation of interneurons was also defective in this model, which may lead to an excitation/inhibition imbalance in PTHS. Overall, sex-dependent differences were detected with more marked effects evidenced in males compared with females. All of this contributes to expand our understanding of PTHS, paralleling the advances of research in autism spectrum disorder and further validating the PTHS mouse model as an important tool to advance preclinical studies.