Boosting tonic inhibition from birth with chronic treatment with the GABAA receptor agonist gaboxadol fully reversed social deficits, restored the integrity of vocal circuits, and the multimodal integration of sensory inputs.
Abstract
In autism spectrum disorder (ASD), children can exhibit a regressive phenotype with loss of previously acquired social and language skills in the first years of life. While the role of the GABAergic system in shaping neural circuits during development has been largely studied, its potential involvement in regressive phenotypes remains unclear. Here, we tracked the social and sensory development in Synapsin2 knockout (Syn2KO) mice, a model of ASD characterized by defective inhibitory tonic current, social deficits, and epilepsy in adulthood. We show that, after a transient early phase of impaired vocalization, young (PND 30) Syn2KO mice reached a normal social behavior. However, social behavior was regressively lost in adult (PND 120) mice, with the absence of vocalizations during the male-female interaction test associated with a drastic degeneration of the preoptic area-periaqueductal gray vocal GABAergic circuit. This deterioration began at earlier stages but was behaviorally latent. Adult Syn2KO mice also displayed sensory dysfunctions and dysregulation of the GABAergic system in the integrative posterior parietal cortex, with hyper-responsiveness of bimodal light- and sound-sensitive neurons that paralleled the social decline. Boosting tonic inhibition from birth with chronic treatment with the GABAA receptor agonist gaboxadol fully reversed social deficits, restored the integrity of vocal circuits, and the multimodal integration of sensory inputs. These results show that social regression in the Syn2KO model is a multiphase process characterized by early signs, a latent period of typical development, and a subsequent decline that can be reversed by enhancing tonic inhibition from development onward.
It is demonstrated that ASD-related alterations are not static but evolve across adulthood, revealing a multi-level reorganization of behavioral, synaptic, and structural features.
Mathieu Thabault, Cloé Fernandes-Gomes, Cloé Alcaraz et al.· Neurobiology of Disease· 0 citations
BACKGROUND
Social dysfunction is a core symptom of autism spectrum disorder (ASD), including fragile X syndrome (FXS), but its underlying neural circuits and molecular mechanisms remain poorly understood. Previous studies have implicated the amygdala and hippocampus in social behaviour, yet the specific pathways and signalling events linking genetic deficits to behavioural dysfunction have not been fully delineated.
METHODS
Using activity-dependent c-Fos mapping, fibre photometry, closed-loop optogenetics, pharmacological inhibition, and shRNA-mediated knockdown, we investigated the role of the BLA-dCA3 projection and ERK signalling in male Fmr1 KO mice, complemented by re-analysis of human ASD snRNA-seq data and whole-cell patch-clamp recordings.
FINDINGS
We found that BLA-dCA3 projecting neurons are aberrantly hyperactivated in Fmr1 KO mice during interactions with both novel and familiar mice, and that closed-loop activation of this pathway in WT mice during familiar interaction impairs social discrimination, whereas its inhibition in KO mice rescues the deficit. Additionally, ERK signalling is upregulated in the BLA of both patients with ASD and Fmr1 KO mice; knocking down FMR1 in the adult BLA recapitulates both the social deficit and ERK hyperactivation, while pharmacological ERK inhibition rescues social behaviour and normalises neuronal hyperexcitability.
INTERPRETATION
These findings pinpoint the BLA-dCA3 circuit and BLA-specific ERK signalling as critical mediators of social discrimination deficits in FXS. Our study establishes a causal link from FMRP loss to circuit dysfunction and ERK pathway dysregulation, and suggests that targeting this pathway may offer a promising strategy for treating social dysfunction in ASD and FXS.
FUNDING
This work was supported by grants from the National Science and Technology Major Project (2025ZD0214701), the National Natural Science Foundation of China (32171014, 31970940, and 32500889), Nanhu Brain-Computer Interface Institute (010904018), and the Zhejiang Provincial Natural Science Foundation of China (LMS25C090004).
The vesicular acetylcholine transporter knockdown (VAChT-KD) mouse is a genetic model of congenital myasthenic syndrome (CMS) characterized by impaired cholinergic transmission at the neuromuscular junction, resulting in presynaptic neuromuscular dysfunction. Here, we performed a longitudinal behavioral analysis to determine the onset and progression of motor deficits across development and adulthood, including potential sex-dependent effects. VAChT-KD mice exhibited early and persistent motor impairments. Neonatal animals showed reduced strength, impaired coordination, and delayed motor development compared to controls, and these deficits persisted into adulthood. Motor performance was consistently impaired in tests of global strength, while other behavioral measures revealed age- and sex-dependent differences. Notably, repeated exposure to motor tasks improved performance in mutant mice, indicating a learning component that partially compensates for underlying deficits. Across behavioral paradigms, genotype and age emerged as the primary determinants of motor performance. Importantly, the identification of early disease onset and measurable functional deficits across development highlights a critical window for therapeutic intervention. These findings support the use of VAChT-KD mice as a translational platform for testing early-stage therapies and underscore the importance of considering behavioral adaptation when designing preclinical studies for neuromuscular disorders.
L. A. Barbosa, K. Santos, Gabriel Marques et al.· Behavioural Brain Research· 0 citations
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits and restricted, repetitive behaviors, often accompanied by motor, cognitive, and anxiety-related alterations. Although ASD is diagnosed more frequently in males than females, females remain underrepresented in preclinical studies, limiting understanding of sex-dependent phenotypes. The BTBR T+ Itpr3tf/J (BTBR) mouse strain is a widely used animal model of ASD, yet its sex-specific behavioral profiles across functional domains remain incompletely characterized. Here, we conducted a systematic, multi-domain behavioral assessment in male and female BTBR mice and wild-type (WT) controls, examining action control, motor learning, social behavior, and anxiety-related exploration. Despite normal acquisition of instrumental responding, BTBR mice exhibited altered action control characterized by reduced habitual responding and persistent sensitivity to action-outcome contingencies following extended habit training, with effects being more pronounced in females. In the accelerating rotarod task, BTBR mice displayed impaired motor learning that was more prominent in males, whereas performance under constant-speed conditions indicated largely preserved baseline motor coordination. Social impairments were dimension-specific: BTBR males showed delayed initiation of social investigation, whereas BTBR females exhibited reduced social engagement. In the elevated plus maze (EPM), overall genotype effects were modest; However, sex-dependent differences emerged within BTBR strain, suggesting altered exploratory behavior and risk-assessment strategies rather than generalized anxiety-like behavior. Together, these findings identify domain- and sex-specific alterations in action selection, motor learning, social behavior and anxiety-related exploration in BTBR mice. These results highlight the importance of sex-stratified analyses in preclinical ASD research and provide a behavioral framework for investigating the mechanisms underlying ASD-relevant phenotypes.
Unknown authors· Frontiers in Behavioral Neur...· 0 citations
Fragile X syndrome (FXS), a leading monogenic cause of intellectual disability and autism- related features, results from loss of fragile X messenger ribonucleoprotein (FMRP). Although early synaptic and cellular abnormalities associated with the loss of FMRP are well described, it remains unclear how these changes shape the maturation of large-scale functional networks, or whether early pharmacological intervention can normalize circuit development. Our previous work demonstrated that cognitive deficits in Fmr1-/y rats emerge during development and can be prevented by brief early-life lovastatin treatment. Here, we asked whether large-scale functional connectivity (FC) shows a similarly dynamic developmental trajectory and whether early intervention alters its emergence. Using longitudinal resting-state functional magnetic resonance imaging (rsfMRI), we found that Fmr1-/y rats displayed an age-dependent FC phenotype, with increased connectivity within the retrosplenial cortex (RSC) at 4 weeks but reduced connectivity within the RSC and distributed brain networks by adulthood compared with wild-type controls. This suggests FC abnormalities emerge over development rather than representing a stable deficit. In contrast to its effects on cognitive measures, brief early-life lovastatin treatment did not prevent the emergence of connectivity abnormalities. Reduced RSC FC was also observed in a small cohort of individuals with FXS (n = 5 per group), supporting further investigation of functional connectivity measures alongside behavioural and molecular endpoints in translational studies of FXS. ONE SENTENCE SUMMARY An age-dependent brain connectivity phenotype in a rat model of FXS is not rescued by lovastatin and aligns with human RSC hypoconnectivity
Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by a microdeletion within chromosome 22q13.3 1–6, and accounts for ∼1-3% of cases of autism spectrum disorders (ASD). Individuals with PMS typically present with neonatal hypotonia, severe speech delay, intellectual disability, motor impairments, and autism-related features, although additional manifestations such as epilepsy, sleep disturbances, and developmental regression are common. As in ASD, there is considerable heterogeneity in cognitive and behavioral impairments in PMS, making it difficult to determine which features arise directly from SHANK3/Shank3 deficiency and how deficits manifest across development. In the present study, we transferred the targeted Shank3 mutation, previously characterized on the Sprague Dawley background, onto the Long-Evans strain and performed a longitudinal behavioral assessment of Shank3-deficient rats from infancy to adulthood. The rats were evaluated for delays in early sensory and motor development, and ultrasonic vocalizations as neonates, social behavior, short term memory and gait as juveniles, and cognitive-executive dysfunction using a touchscreen-based visual discrimination and reversal learning task as adults. Despite profound reductions and/or complete loss of Shank3 protein expression, heterozygous and homozygous male and female rats showed normal physical and neurological reflexes across development, yet female Shank3 knockout pups showed a selective reduction in distress-associated ultrasonic vocalizations. As juveniles, subtle abnormalities emerged in short-term memory and limb coordination, while social preference for novelty and recognition was normal. Prominent behavioral abnormalities were observed in adults characterized by rapid and error-prone responding to visual stimuli during discrimination learning and reversal. These data suggest that rats with complete or partial Shank3 deficiency produce a selective behavioral profile in which high-order cognitive dysfunction is more pronounced than deficits in basic sensorimotor or select social behaviors. More broadly, these findings highlight executive dysfunction as a key consequence of the loss of Shank3. For the first time, we report the loss of Shank3 expression on a Long-Evans background strain as a valuable translational tool for investigating cognitive dysfunction and therapeutic windows in Shank3-associated disorders.
Anna C. Pearson, T. Drazan, Sean P. Bradley et al.· bioRxiv· 0 citations
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