Biology subjects

Baggio, S.

Publications and source records attributed to Baggio, S..

3 recordsLinked to original sources

bioRxiv2025

β-catenin-independent regulation by TCF7L2 underlies isoform redundancy during embryonic thalamic development

Alternative promoter usage generates multiple transcription factor isoforms during brain development, yet their functional significance remains poorly defined. One such example is TCF7L2, a transcription factor critical for the development of the thalamus and recurrently affected by de novo mutations in autism spectrum disorder. TCF7L2 exists in two isoforms driven from different promoters: the long isoform (L-TCF7L2) with the {beta}-catenin-binding domain, and the shorter isoform (S-TCF7L2), lacking this domain and classically considered a dominant-negative regulator of the L isoform. We investigated the role of TCF7L2 isoforms in thalamic development using total and isoform-specific knockout strategies. Integrated phenotypic and transcriptomic analyses revealed functional redundancy of TCF7L2 isoforms during embryogenesis. {beta}-catenin subcellular localization and chromatin occupancy uncovered a developmental switch in TCF7L2 activity, from a {beta}-catenin-independent and isoform-redundant mode in the embryonic thalamus to a {beta}-catenin-dependent program postnatally. More broadly, these findings point to distinct embryonic and postnatal regulatory strategies, with alternative promoter usage potentially supporting robust availability of regulatory proteins during brain development.

neuroscience↗

bioRxiv2025

The Role of TCF7L2 in Regulating Energy Metabolism in Thalamocortical Circuitry and its Broader Impact on Social Behavior

Psychiatric and metabolic disorders often co-occur. While shared genetic factors and cellular dysfunctions are implicated, the underlying molecular mechanisms remain poorly understood. TCF7L2, a risk gene for type 2 diabetes and autism spectrum disorder, is highly expressed in the thalamus--a brain region extensively interconnected with the cortex, playing a key role in sensory processing, motor control, and behavioral regulation. Given its known role as a transcription factor regulating systemic energy metabolism, we explored its potential contribution to brain metabolism and behavior. To this end, we used a conditional knockout model with postnatal TCF7L2 loss in the thalamus and partial deficiency in the pancreas. Tcf7l2 knockout mice exhibited social deficits and reduced motor habituation. In parallel, they also developed systemic glucose intolerance, modelling the psychiatric-metabolic comorbidity. Thalamic depletion of TCF7L2 resulted in elevated inhibitory phosphorylation of the pyruvate dehydrogenase --an enzymatic gatekeeper for pyruvate utilization in energy production--in the thalamus and cortex. This was accompanied by altered thalamic and cortical metabolism, characterized by reduced efficiency of pyruvate oxidation alongside enhanced oxidation of fatty acids and ketone bodies. Notably, a ketogenic diet alleviated metabolic dysregulation in the brain and normalized some social behaviors in knockout mice. These findings suggest that impaired energy metabolism in the thalamocortical circuitry may represent one of the pathogenic mechanisms underlying neuropsychiatric symptoms.

neuroscience↗

bioRxiv2019

Linking alpha oscillations, attention and inhibitory control in adult ADHD with EEG neurofeedback

Abnormal patterns of electrical oscillatory activity have been repeatedly described in adult ADHD. In particular, the alpha rhythm (8-12 Hz), known to be modulated during attention, has previously been considered as candidate biomarker for ADHD. In the present study, we asked adult ADHD patients to self-regulate their own alpha rhythm using neurofeedback (NFB), in order to examine the modulation of alpha oscillations on attentional performance and brain plasticity. Twenty-five adult ADHD patients and 22 healthy controls underwent a 64-channel EEG-recording at resting-state and during a Go/NoGo task, before and after a 30 min-NFB session designed to reduce (desynchronize) the power of the alpha rhythm. Alpha power was compared across conditions and groups, and the effects of NFB were statistically assessed by comparing behavioral and EEG measures pre-to-post NFB. Firstly, we found that relative alpha power was attenuated in our ADHD cohort compared to control subjects at baseline and across experimental conditions, suggesting a signature of cortical hyper-activation. Both groups demonstrated a significant and targeted reduction of alpha power during NFB. Interestingly, we observed a post-NFB increase in resting-state alpha (i.e. rebound) in the ADHD group, which restored alpha power towards levels of the normal population. Importantly, the degree of post-NFB alpha normalisation during the Go/NoGo task correlated with individual improvements in motor inhibition (i.e. reduced commission errors and slower reaction times in NoGo trials) only in the ADHD group. Overall, our findings offer novel supporting evidence implicating alpha oscillations in inhibitory control, as well as their potential role in the homeostatic regulation of cortical excitatory/inhibitory balance.\n\nHighlightsO_LIResting alpha power is reduced in adult ADHD suggesting cortical hyper-activation\nC_LIO_LIAdult ADHD patients successfully reduce alpha power during neurofeedback\nC_LIO_LIA post-neurofeedback rebound normalizes alpha power in adult ADHD\nC_LIO_LIAlpha power rebound correlates with improvement of inhibitory control in adult ADHD\nC_LI

neuroscience↗