Biology subjects

Gatto, G.

Publications and source records attributed to Gatto, G..

9 recordsLinked to original sources

bioRxiv2026

Mitochondrial dysfunction plays a key role in premature musculoskeletal aging in hypochondroplasia mouse model

Hypochondroplasia (HCH) is a mild form of chondrodysplasia, caused by variants in fibroblast growth factor receptor 3 (FGFR3). Today, the biological mechanism underlying musculoskeletal aging in HCH remains largely unknown. In this study, we show that Hch mice exhibit phenotypic traits of bone fragility and accelerated age-dependent articular cartilage and subchondral bone changes. Hch mice also presented decreased muscle strength and reduction in muscle fibers size. Furthermore, proteomics analyses of the cortical bone revealed that Hch mice follow a different aging trajectory than control. FGFR3 mutation leads to a premature boost of the mitochondrial processes forcing the mutant to reach a physiological state much earlier than the control. Together, these findings demonstrate that aging in Hch mice is accompanied by bone fragility and osteoarthritis-like changes. Proteomics analyses highlighted the key role for mitochondria in the cortical bone of Hch mice, providing insight into the mechanisms underlying premature aging in HCH.

genetics↗

bioRxiv2025

The spinal premotor network driving scratching flexor and extensor alternation

Rhythmic motor behaviors are generated by neural networks termed central pattern generators (CPGs). Although locomotor CPGs have been extensively characterized, it remains unknown how the neuronal populations composing them interact to generate adaptive rhythms. We explored the non-linear cooperation dynamics among the three main populations of ipsilaterally projecting spinal CPG neurons - V1, V2a, V2b neurons - in scratch reflex rhythmogenesis. Ablation of all three neuronal subtypes reduced the oscillation frequency. Activation of excitatory V2a neurons enhanced the oscillation frequency, while activating inhibitory V1 neurons caused atonia. These findings required the development of a novel neuromechanical model that consists of flexor and extensor modules coupled via inhibition, in which rhythm in each module is generated by self-bursting excitatory populations and accelerated by intra-module inhibition. Inter-module inhibition coordinates the phases of flexor and extensor activity and slows the oscillations, while facilitation mechanisms in excitatory neurons explain the V2a activation-driven increase in frequency.

neuroscience↗

bioRxiv2024

The transcriptomic landscape of spinal V1 interneurons reveals a role for En1 in specific elements of motor output

Neural circuits in the spinal cord are composed of diverse sets of interneurons that play crucial roles in shaping motor output. Despite progress in revealing the cellular architecture of the spinal cord, the extent of cell type heterogeneity within interneuron populations remains unclear. Here, we present a single-nucleus transcriptomic atlas of spinal V1 interneurons across postnatal development. We find that the core molecular taxonomy distinguishing neonatal V1 interneurons perdures into adulthood, suggesting conservation of function across development. Moreover, we identify a key role for En1, a transcription factor that marks the V1 population, in specifying one unique subset of V1Pou6f2 interneurons. Loss of En1 selectively disrupts the frequency of rhythmic locomotor output but does not disrupt flexion/extension limb movement. Beyond serving as a molecular resource for this neuronal population, our study highlights how deep neuronal profiling provides an entry point for functional studies of specialized cell types in motor output.

neuroscience↗

bioRxiv2024

Endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses

The selective loss of cerebellar Purkinje cells is a hallmark of various neurodegenerative movement disorders, yet the precise mechanism driving their degeneration remains enigmatic. Here, we show that the endocytic adaptor protein complex 2 (AP-2) is essential for the survival of Purkinje cells. Employing a multidisciplinary approach encompassing mouse genetics, viral tracing, ex vivo calcium imaging, and kinematic analysis, we demonstrate that mice lacking the {micro}-subunit of AP-2 in cerebellar Purkinje cells exhibit early-onset ataxia associated with progressive Purkinje cell degeneration. Importantly, we uncover that synaptic input dysfunctions, characterized by a predominance of parallel fiber (PF) over climbing fiber (CF) synapses, precede Purkinje cell loss. Mechanistically, we find that AP-2 localizes to Purkinje cell dendrites, where it interacts with the PF synapse-enriched protein GRID2IP. The loss of AP-2 results in proteasome-dependent degradation of GRID2IP and accumulation of the glutamate {delta}2 receptor (GLUR{delta}2) in distal Purkinje cell dendrites, leading to an excess of PF synapses while CF synapses are drastically reduced. The overrepresentation of PF synaptic input induces Purkinje cell hyperexcitation, which can be alleviated by enhancing synaptic glutamate clearance using the antibiotic ceftriaxone. Our findings demonstrate the critical role of AP-2 in preventing motor gait dysfunctions by regulating GRID2IP levels in Purkinje cells, thereby preserving the equilibrium of PF and CF synaptic inputs in a cell-autonomous manner.

neuroscience↗

bioRxiv2024

AutoGaitA - Automated Gait Analysis in Python

Individual behaviours require the nervous system to execute specialised motor programs, each characterised by unique patterns of coordinated movements across body parts. Deep learning approaches for body-posture tracking have facilitated the analysis of such motor programs. However, translating the resulting time-stamped coordinate datasets into meaningful kinematic representations of motor programs remains a long-standing challenge. We developed the versatile quantitative framework AutoGaitA (Automated Gait Analysis), a Python toolbox that enables comparisons of motor programs at multiple levels of granularity and across tracking methods, species and behaviours. AutoGaitA allowed us to demonstrate that flies, mice, and humans, despite divergent biomechanics, converge on the age-dependent loss of propulsive strength, and that, in mice, locomotor programs adapt as an integrated function of both age and task difficulty. AutoGaitA represents a truly universal framework for robust analyses of motor programs and changes thereof in health and disease, and across species and behaviours.

animal behavior and cognition↗

bioRxiv2024

Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity

Dysfunctions in autophagy, a highly conserved cellular mechanism responsible for the degradation of intracellular components within lysosomes, often result in neurodegeneration. The neuroprotective effect of autophagy varies across neuronal subtypes, and the mechanisms of selective vulnerability of neurons to autophagy dysfunction are currently unknown. Utilizing a mouse model of ATG5 deficiency in inhibitory neurons and a comprehensive approach, including PET imaging, metabolomics, stable-isotope labeling studies, and live cell imaging, we establish that autophagy contributes to the survival of cerebellar Purkinje cells (PCs) by safeguarding their glycolytic activity. We show that the core autophagy protein ATG5 downregulates the levels of the glucose transporter 2 (GLUT2) during brain maturation. Autophagy-deficient PCs exhibit increased glucose uptake, along with elevated levels of glycolytic intermediates and methylglyoxal-modified proteins. We propose lysophosphatidic acid and serine as glycolytic intermediates inducing PC death and demonstrate that deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and restores their ataxic gait. Taken together, this study reveals a novel neuroprotective role of autophagy in preventing excessive glycolytic metabolism in the brain.

neuroscience↗

bioRxiv2023

A spinal synergy of excitatory and inhibitory neurons coordinates ipsilateral body movements

Innate and goal-directed movements require a high-degree of trunk and appendicular muscle coordination to preserve body stability while ensuring the correct execution of the motor action. The spinal neural circuits underlying motor execution and postural stability are finely modulated by propriospinal, sensory and descending feedback, yet how distinct spinal neuron populations cooperate to control body stability and limb coordination remains unclear. Here, we identified a spinal microcircuit composed of V2 lineage-derived excitatory (V2a) and inhibitory (V2b) neurons that together coordinate ipsilateral body movements during locomotion. Inactivation of the entire V2 neuron lineage does not impair intralimb coordination but destabilizes body balance and ipsilateral limb coupling, causing mice to adopt a compensatory festinating gait and be unable to execute skilled locomotor tasks. Taken together our data suggest that during locomotion the excitatory V2a and inhibitory V2b neurons act antagonistically to control intralimb coordination, and synergistically to coordinate forelimb and hindlimb movements. Thus, we suggest a new circuit architecture, by which neurons with distinct neurotransmitter identities employ a dual-mode of operation, exerting either synergistic or opposing functions to control different facets of the same motor behavior.

neuroscience↗

bioRxiv2023

Myomatrix arrays for high-definition muscle recording

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous systems actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous systems motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

neuroscience↗

bioRxiv2019

Association of extent of cannabis use and psychotic like intoxication experiences in a multi-national sample of First Episode Psychosis patients and controls

AimsFirst Episode Psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in FEP patients and controls and whether this differs between groups. MethodsWe analysed data on lifetime cannabis using patients (n=655) and controls (n=654) across 15 sites from six countries in the EU-GEI study (2010-2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use. ResultsCaseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences, independent of other experiences (p[≤]0.001). For psychotic-like experiences there was a significant interaction for caseness x frequency of use (p<0.001) and caseness x money spent on cannabis (p=0.001) such that FEP patients had increased experiences at increased levels of use compared to controls. There was no similar significant interaction for euphoric experiences (p>0.5). Conclusions and RelevanceFEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher frequency and amount of cannabis use compared to controls. This suggests a specific psychotomimetic response in patients related particularly to heavy cannabis use.

neuroscience↗