A groundbreaking study published in Translational Psychiatry has revealed a remarkable discovery about the brain connectivity patterns in Shank3 mice, a widely utilized animal model for autism spectrum disorder (ASD). The research, led by Montagni, Ambrosone, Martello, and colleagues, uncovers age-dependent cortical overconnectivity that intriguingly can be reversed through anesthesia. This finding not only reshapes our understanding of neurodevelopmental disorders but also opens new avenues for potential therapeutic interventions targeting synaptic and network dysfunction in ASD.
Shank3, a scaffold protein encoded by the SHANK3 gene, plays a crucial role in synaptic formation and maintenance, especially within excitatory glutamatergic synapses. Mutations or deletions of SHANK3 have been implicated in Phelan-McDermid Syndrome and are often identified in individuals with ASD, making Shank3-deficient mice an essential model for dissecting the neurobiological underpinnings of these conditions. Previous research predominantly focused on synaptic deficits and behavioral abnormalities in these mice; however, Montagni et al. provide the first comprehensive exploration into the dynamic nature of cortical connectivity changes during development, highlighting an unexpected reversal capacity.
Through the application of advanced neuroimaging techniques, specifically in vivo two-photon calcium imaging in awake behaving mice, the study tracked cortical network activity across various developmental stages. Early postnatal periods displayed heightened cortical connectivity compared to wild-type controls, a phenomenon referred to as “overconnectivity.” This aberrant synaptic exuberance persisted into adolescence but, critically, altered as the animals aged, indicating a plastic yet pathological trajectory in cortical circuit organization. The hyper-connected state aligns with clinical observations in some ASD patients where atypical neural synchrony and functional connectivity have been documented via human neuroimaging studies.
The researchers took an innovative approach by administering general anesthesia at key developmental windows to Shank3 mutant mice. Anesthesia, commonly employed to transiently suppress neural activity, effectively normalized the excessive cortical connections when applied in early adulthood. The underlying mechanisms are believed to involve modulation of synaptic efficacy and network excitability, potentially rebalancing excitatory-inhibitory homeostasis that is disrupted in ASD models. This demonstrates that even established cortical overconnectivity is not rigid but malleable under specific physiological conditions.
Electrophysiological recordings complemented the imaging data, revealing that anesthesia induces a shift in synaptic transmission dynamics, particularly in glutamatergic pathways. The study highlights the reversal of elevated miniature excitatory postsynaptic currents (mEPSCs) frequency and amplitude toward typical ranges after anesthetic exposure. This synaptic recalibration coincides with normalized gamma oscillations, which are critically involved in higher cognitive functions and are known to be perturbed in ASD. Such findings underscore the multifaceted impact of anesthesia beyond its sleep-inducing properties, implicating it as a potential modulator of synaptic plasticity.
Molecular analyses elucidated the changes occurring at the receptor level, noting alterations in NMDA and AMPA receptor subunit expression post-anesthesia. These receptors govern excitatory neurotransmission and plasticity, and their dysregulation is a hallmark of ASD synaptic pathology. Montagni et al. found a restoration of receptor subunit ratios closer to wild-type profiles, suggesting that anesthesia prompts homeostatic adjustments rather than merely suppressing activity. This mechanistic insight bridges functional changes with molecular substrates, reinforcing the therapeutic potential of targeted neuromodulation.
The implications of this work extend to the ongoing debate on the role of network connectivity in ASD. Hypo- and hyper-connectivity models have both been proposed, often depending on age, brain region, and methodology. Here, the authors propose a developmental shift in connectivity abnormalities, with early hyperconnectivity leading to network imbalance that could underlie cognitive and behavioral symptoms. Their data advocate for a nuanced view acknowledging the fluidity of neural circuits and the possibility of correcting maladaptive connectivity with appropriate interventions.
Montagni and colleagues emphasize that the reversal of cortical overconnectivity by anesthesia is transient but significant, opening questions about the longevity and functional consequences of such treatments. Future studies will need to explore repeated or chronic modulation strategies, as well as translate findings into clinical frameworks. Although anesthesia itself is not a practical therapy, understanding its mechanistic effects may inspire non-invasive neuromodulatory approaches—like transcranial magnetic stimulation or targeted pharmacological agents—that mimic these synaptic adjustments.
In addition to therapeutic relevance, the study enhances our comprehension of neurodevelopmental timing in circuit formation. The age-dependent nature of connectivity changes in Shank3 mice aligns with critical periods of synaptic pruning and network refinement in typical brain development. Disruptions during these windows seem pivotal in ASD pathogenesis. By identifying these phases, the research underscores the importance of early diagnosis and intervention, potentially allowing for recalibration of pathological neural states before symptom onset.
The authors further discuss how anesthesia-induced modulation of cortical circuits might relate to clinical observations of altered sensory processing and cognitive function in individuals undergoing general anesthesia, suggesting a delicate balance between neural suppression and plasticity. Their findings advocate for a reevaluation of anesthesia’s neurophysiological impact, particularly in vulnerable populations such as children with neurodevelopmental disorders, where both risks and benefits must be carefully weighed.
Moreover, this research paves the way for exploring the interface between genetics, synaptic pathology, and network dynamics. Since SHANK3 mutations are just one component among many ASD-linked genetic variants, the capacity to reverse pathological connectivity in this model raises hope that other genetic forms of ASD may exhibit similar neural plasticity. The study invites broader investigations into genotype-specific circuit abnormalities and their amenability to neuromodulatory treatments.
The study was methodologically rigorous, employing longitudinal designs and sophisticated in vivo techniques that captured real-time changes in the living brain. This represents a significant advancement over postmortem or ex vivo analyses that fail to reflect dynamic neural processes. By integrating imaging, electrophysiology, and molecular biology, the authors provide a robust, multidisciplinary perspective crucial for translating basic science into clinical innovation.
Public and scientific interest in this research is amplified by its potential to revolutionize how we conceive brain plasticity in neurodevelopmental disorders. The notion that abnormal connectivity associated with autism can not only be mapped but also reversed—even temporarily—challenges deterministic views of genetic brain disorders and injects optimism into the search for effective therapies.
In conclusion, Montagni et al.’s discovery of anesthesia-reversible cortical overconnectivity in Shank3 mutant mice marks a paradigm shift in ASD research. It reveals a dynamic and manipulable neural landscape, encouraging the development of neuromodulation-based strategies aimed at correcting network dysfunction. While clinical translation requires additional studies, including safety and efficacy assessments, this work solidifies the value of animal models in elucidating complex brain disorders and highlights novel intervention windows that could ultimately improve outcomes for individuals affected by autism spectrum disorder.
Subject of Research: Age-dependent cortical overconnectivity and its reversal by anesthesia in Shank3 mutant mice, a model of autism spectrum disorder.
Article Title: Age-dependent cortical overconnectivity in Shank3 mice is reversed by anesthesia.
Article References:
Montagni, E., Ambrosone, M., Martello, A. et al. Age-dependent cortical overconnectivity in Shank3 mice is reversed by anesthesia. Transl Psychiatry 15, 154 (2025). https://doi.org/10.1038/s41398-025-03377-5
Image Credits: AI Generated
