1. Catalano F, Santorelli D, Astegno A, Favaretto F, D’Abramo M, Del Giudice A, De Sciscio ML, Troilo F, Giardina G, Di Matteo A, Travaglini-Allocatelli C. Conformational and dynamic properties of the KH1 domain of FMRP and its fragile X syndrome linked G266E variant. Biochim Biophys Acta Proteins Proteom. 2024: 141019.

The Fragile X messenger ribonucleoprotein (FMRP) is a complex, multi-domain protein involved in interactions with various macromolecules, including proteins and coding/non-coding RNAs. The three KH domains (KH0, KH1 and KH2) within FMRP are recognized for their roles in mRNA binding. In the context of Fragile X syndrome (FXS), over-and-above CGG triplet repeats expansion, three specific point mutations have been identified, each affecting one of the three KH domains ((R138)QKH0, (G266)EKH1, and (I304N)KH2) resulting in the expression of non-functional FMRP. This study aims to elucidate the molecular mechanism underlying the loss of function associated with the (G266E)KH1 pathological variant. We investigate the conformational and dynamical properties of the isolated KH1 domain and the two KH1 site-directed mutants (G266E)KH1 and (G266A)KH1. Employing a combined in vitro and in silico approach, we reveal that the (G266E)KH1 variant lacks the characteristic features of a folded domain. This observation provides an explanation for functional impairment observed in FMRP carrying the G266E mutation within the KH1 domain, as it renders the domain unable to fold properly. Molecular Dynamics simulations suggest a pivotal role for residue 266 in regulating the structural stability of the KH domains, primarily through stabilizing the α-helices of the domain. Overall, these findings enhance our comprehension of the molecular basis for the dysfunction associated with the (G266E)KH1 variant in FMRP.

Lien vers le texte intégral (Open Access ou abonnement)

2. Das S, Zomorrodi R, Kirkovski M, Hill AT, Enticott PG, Blumberger DM, Rajji TK, Desarkar P. Atypical alpha band microstates produced during eyes-closed resting state EEG in autism. Prog Neuropsychopharmacol Biol Psychiatry. 2024; 131: 110958.

Electroencephalogram (EEG) microstates, which represent quasi-stable patterns of scalp topography, are a promising tool that has the temporal resolution to study atypical spatial and temporal networks in autism spectrum disorder (ASD). While current literature suggests microstates are atypical in ASD, their clinical utility, i.e., relationship with the core behavioural characteristics of ASD, is not fully understood. The aim of this study was to examine microstate parameters in ASD, and examine the relationship between these parameters and core behavioural characteristics in ASD. We compared duration, occurrence, coverage, global explained variance percentage, global field power and spatial correlation of EEG microstates between autistic and neurotypical (NT) adults. Modified k-means cluster analysis was used on eyes-closed, resting state EEG from 30 ASD (10 females, 28.97 ± 9.34 years) and 30 age-equated NT (13 females, 29.33 ± 8.88 years) adults. Five optimal microstates, A to E, were selected to best represent the data. Five microstate maps explaining 80.44% of the NT and 78.44% of the ASD data were found. The ASD group was found to have atypical parameters of microstate A, C, D, and E. Of note, all parameters of microstate C in the ASD group were found to be significantly less than NT. While parameters of microstate D, and E were also found to significantly correlate with subscales of the Ritvo Autism Asperger Diagnostic Scale – Revised (RAADS-R), these findings did not survive a Bonferroni Correction. These findings, in combination with previous findings, highlight the potential clinical utility of EEG microstates and indicate their potential value as a neurophysiologic marker that can be further studied.

Lien vers le texte intégral (Open Access ou abonnement)

3. Deng Y, Ma L, Du Z, Ma H, Xia Y, Ping L, Chen Z, Zhang Y. The Notch1/Hes1 pathway regulates Neuregulin 1/ErbB4 and participates in microglial activation in rats with VPA-induced autism. Prog Neuropsychopharmacol Biol Psychiatry. 2024; 131: 110947.

The core clinical characteristics of autism, which is a neurodevelopmental disease, involve repetitive behavior and impaired social interactions. Studies have shown that the Notch and Neuregulin1 (NRG1) signaling pathways are abnormally activated in autism, but the mechanism by which these two signaling pathways interact to contribute to the progression of autism has not been determined. Our results suggest that the levels of Notch1, Hes1, NRG1, and phosphorylated ErbB4 in the cerebellum (CB), hippocampus (HC), and prefrontal cortex (PFC) were increased in rats with valproic acid (VPA)-induced autism compared to those in the Con group. However, 3, 5-difluorophenyl-L-alanyl-L-2-phenylglycine tert-butyl (DAPT), which is a Notch pathway inhibitor, ameliorated autism-like behavioral abnormalities and decreased the protein levels of NRG1 and phosphorylated ErbB4 in rats with VPA-induced autism; these results demonstrated that the Notch1/Hes1 pathway could participate in the pathogenesis of autism by regulating the NRG1/ErbB4 signaling pathway. Studies have shown that the Notch pathway regulates microglial differentiation and activation during the onset of neurological disorders and that microglia affect autism-like behavior via synaptic pruning. Therefore, we hypothesized that the Notch1/Hes1 pathway could regulate the NRG1/ErbB4 pathway and thus participate in the development of autism by regulating microglial functions. The present study showed that AG1478, which is an ErbB4 inhibitor, ameliorated the autism-like behaviors in a VPA-induced autism rat model, reduced abnormal microglial activation, and decreased NRG1 and Iba-1 colocalization; however, AG1478 did not alter Notch1/Hes1 activity. These results demonstrated that Notch1/Hes1 may participate in the microglial activation in autism by regulating NRG1/ErbB4, revealing a new mechanism underlying the pathogenesis of autism.

Lien vers le texte intégral (Open Access ou abonnement)

4. Guo X, Zhang X, Liu J, Zhai G, Zhang T, Zhou R, Lu H, Gao L. Resolving heterogeneity in dynamics of synchronization stability within the salience network in autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2024; 131: 110956.

BACKGROUND: Heterogeneity in resting-state functional connectivity (FC) are one of the characteristics of autism spectrum disorder (ASD). Traditional resting-state FC primarily focuses on linear correlations, ignoring the nonlinear properties involved in synchronization between networks or brain regions. METHODS: In the present study, the cross-recurrence quantification analysis, a nonlinear method based on dynamical systems, was utilized to quantify the synchronization stability between brain regions within the salience network (SN) of ASD. Using the resting-state functional magnetic resonance imaging data of 207 children (ASD/typically-developing controls (TC): 105/102) in Autism Brain Imaging Data Exchange database, we analyzed the laminarity and trapping time differences of the synchronization stability between the ASD subtype derived by a K-means clustering analysis and the TC group, and examined the relationship between synchronization stability and the severity of clinical symptoms of the ASD subtypes. RESULTS: Based on the synchronization stability within the SN of ASD, we identified two subtypes that showed opposite changes in synchronization stability relative to the TC group. In addition, the synchronization stability of ASD subtypes 1 and 2 can predict the social interaction and communication impairments, respectively. CONCLUSIONS: These findings reveal that ASD subgroups with different patterns of synchronization stability within the SN appear distinct clinical symptoms, and highlight the importance of exploring the potential neural mechanism of ASD from a nonlinear perspective.

Lien vers le texte intégral (Open Access ou abonnement)

5. Jin T, Huang W, Pang Q, Cao Z, Xing D, Guo S, Zhang T. Genetically identified mediators associated with increased risk of stroke and cardiovascular disease in individuals with autism spectrum disorder. J Psychiatr Res. 2024; 174: 172-80.

Growing evidence suggested that individuals with autism spectrum disorder (ASD) associated with stroke and cardiovascular disease (CVD). However, the causal association between ASD and the risk of stroke and CVD remains unclear. To validate this, we performed two-sample Mendelian randomization (MR) and two-step mediation MR analyses, using relevant genetic variants sourced from the largest genome-wide association studies (GWASs). Two-sample MR evidence indicated causal relationships between ASD and any stroke (OR = 1.1184, 95% CI: 1.0302-1.2142, P < 0.01), ischemic stroke (IS) (OR = 1.1157, 95% CI: 1.0237-1.2160, P = 0.01), large-artery atherosclerotic stroke (LAS) (OR = 1.2902, 95% CI: 1.0395-1.6013, P = 0.02), atrial fibrillation (AF) (OR = 1.0820, 95% CI: 1.0019-1.1684, P = 0.04), and heart failure (HF) (OR = 1.1018, 95% CI: 1.0007-1.2132, P = 0.05). Additionally, two-step mediation MR suggested that type 2 diabetes mellitus (T2DM) partially mediated this effect (OR = 1.14, 95%CI: 1.02-1.28, P = 0.03). The mediated proportion were 10.96% (95% CI: 0.58%-12.10%) for any stroke, 11.77% (95% CI: 10.58%-12.97%) for IS, 10.62% (95% CI: 8.04%-13.20%) for LAS, and 7.57% (95% CI: 6.79%-8.36%) for HF. However, no mediated effect was observed between ASD and AF risk. These findings have implications for the development of prevention strategies and interventions for stroke and CVD in patients with ASD.

Lien vers le texte intégral (Open Access ou abonnement)

6. Maisterrena A, de Chaumont F, Longueville JE, Balado E, Ey E, Jaber M. Female mice prenatally exposed to valproic acid exhibit complex and prolonged social behavior deficits. Prog Neuropsychopharmacol Biol Psychiatry. 2024; 131: 110948.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized mainly by deficits in social communication and stereotyped and restricted behavior and interests with a male to female bias of 4.2/1. Social behavior in ASD animal models is commonly analyzed in males, and seldomly in females, using the widely implemented three-chambers test procedure. Here, we implemented a novel procedure, the Live Mouse Tracker (LMT), combining artificial intelligence, machine learning procedures and behavioral measures. We used it on mice that were prenatally exposed to valproic acid (VPA) (450 mg/kg) at embryonic day 12.5, a widely recognized and potent ASD model that we had previously extensively characterized. We focused on female mice offspring, in which social deficits have been rarely documented when using the 3-CT procedure. We recorded several parameters related to social behavior in these mice, continuously for three days in groups of four female mice. Comparisons were made on groups of 4 female mice with the same treatment (4 saline or 4 VPA) or with different treatments (3 saline and 1 VPA). We report that VPA females show several types of social deficits, which are different in nature and magnitude in relation with time. When VPA mice were placed in the LMT alongside saline mice, their social deficits showed significant improvement as early as 1 h from the start of the experiment, lasting up to 3 days throughout the duration of the experiment. Our findings suggest that ASD may be underdiagnosed in females. They also imply that ASD-related social deficits can be ameliorated by the presence of typical individuals.

Lien vers le texte intégral (Open Access ou abonnement)