A group of scientists led by Claudia Bagni, in a collaboration between the Department of Biomedicine and Prevention of the University of Rome Tor Vergata and the Department of Fundamental Neurosciences of the University of Lausanne in Switzerland, and other international teams between the USA, England , Belgium and the Netherlands, discovered “a new molecular mechanism underlying the deficit of flexibility in social behavior” which characterizes Fragile X Syndrome (Fxs), the most common form of hereditary intellectual disability and the main monogenetic cause of autism. Thanks to the study, partly funded by Telethon and published in ‘Neuron’, “possible therapeutic targets have been identified to help improve behavioral defects due to reduced flexibility, present in these two conditions and in other neurological pathologies”, explain the University of Tor Vergata.
The authors – reads a note – have identified the key role that a part of the brain, called the ‘striatum’, plays by regulating flexibility in behavior and learning in the context of fragile X syndrome. Cognitive flexibility allows us to adapt our behavior to achieve daily goals, to switch quickly from one concept to another or to adapt easily in a new environment. It also reflexively affects emotional and social cognition, helping us to better understand the emotions of the people around us.
Using a mouse model for the study of Fxs, the researchers have revealed “the molecular mechanism underlying this alteration: it can be traced back to changes in a protein called actin – says Bagni – which is capable of forming filaments that lengthen and shorten helping the structure, movement and functionality of the contact points of neuronal cells, called synapses.Understanding the spatio-temporal (dys)regulation of the protein composition of synapses turns out to be of extreme importance to unravel how synapses evolve during development and integrate into the mature brain network”.
Fxs – recall from Tor Vergata – is due to the absence of the protein Fragile X Messenger Ribonucleoprotein (Fmrp), which regulates the metabolism of many messenger RNAs (mRNAs) coding for proteins, some of which are present in the synapses and essential for correct development and neuronal functioning. In recent years, genetic studies on neurodevelopmental disorders have shown how a dysfunction of synaptic proteins contributes in a decisive way to the pathogenesis of a class of neurological diseases called precisely synaptopathies, to which Fragile X Syndrome and autism belong.
“We discovered – Bagni details – that in the striatum of model mice for the study of Fxs the proteins of the cytoskeleton located in the dense area of the post-synaptic membrane are expressed in a reduced way with consequences in the communication between nerve cells, following the behavioral changes which require good adaptability and flexibility. These molecular and cellular dysfunctions are at the basis of greater cognitive and behavioral rigidity, typical of FXS”. The team demonstrated that following an enhancement of the elongation and movement of the actin filaments, a restoration of the synaptic structure is observed with an effect on the behavior of the animal.
“The results of this study – remarks Bagni – highlight the importance of actin, such a fundamental protein in all our cells, capable of having a specific action at the level of neuronal connections in a very precise region of our brain, the striatum, in fact.This mechanism underlies the regulation of flexibility and behavioral adaptability, highlighting how the striatum is a crucial region for one of the main behavioral deficits observed in individuals with FXS and autism.With this study we provide a molecular explanation for this behavioral deficiency and we suggest that possible specific treatment, targeting the striatum brain region, either pharmacologically or through programs aimed at developing and enhancing cognitive flexibility, could ameliorate this maladaptive behavior in Fragile X Syndrome and possibly in other neurological conditions that share reduced cognitive flexibility with Fxs”.