Biology subjects

Cambiaghi, M.

Publications and source records attributed to Cambiaghi, M..

5 recordsLinked to original sources

bioRxiv2026

Oligodendroglial deletion of the microcephaly gene Cit-k disrupts cortical connectivity and cognitive function

Neurodevelopmental disorders (NDDs) are increasingly recognized as disorders of brain connectivity and circuit dysfunction. Growing evidence suggests that glial cell and myelin abnormalities may actively contribute to these alterations. Yet, they have been often considered secondary consequences of impaired neuronal development rather than primary drivers of circuit dysfunction. Primary autosomal recessive microcephaly type 17 (MCPH17) is a severe NDD caused by mutations in the CIT gene, encoding Citron kinase (CIT-K). The disease is associated with cognitive and motor deficits, epilepsy susceptibility, and marked hypomyelination in both patients and mouse models, suggesting a contribution of oligodendroglial dysfunction to disease pathophysiology. Here, we investigated the specific role of oligodendroglial Cit-k loss using Sox10Cre;Cit-kfl/fl mice, in which Cit-k is selectively deleted in oligodendrocyte-lineage cells. Mutant mice displayed impaired forebrain myelination at juvenile stages and persistent cortical hypomyelination in adulthood. Despite preserved gross motor function, adult mutants showed deficits in fine motor control, working and recognition memory, and auditory fear memory. These impairments were associated with altered cortico-cortical and cortico-hippocampal functional connectivity. Moreover, consistent with the clinical MCPH17 phenotype, mutant mice exhibited increased susceptibility to kainate-induced seizures. Together, our findings show that oligodendroglial Cit-k loss and the resulting hypomyelination are sufficient to produce long-lasting neurological and behavioral impairments independently of primary neuronal defects. These results identify oligodendrocytes as active contributors to MCPH17 and support a broader role for myelin abnormalities in NDDs. HighlightsO_LICit-k deletion in oligodendroglia disrupts forebrain myelination C_LIO_LICortical hypomyelination persists in adult mutant mice C_LIO_LIMutant mice show deficits in motor control and memory C_LIO_LICortico-cortical and cortico-hippocampal connectivity are altered C_LIO_LIligodendrocytes contribute to microcephaly-associated dysfunctions C_LI

neuroscience↗

bioRxiv2026

A knock-in model of severe GUCA1A cone-rod dystrophy reveals retinal network dysfunction beyond phototransduction

Autosomal dominant cone-rod dystrophy caused by GUCA1A mutations is generally viewed as a disorder of phototransduction, yet the mechanisms linking photoreceptor dysfunction to progressive vision loss remain unclear. Here, using a knock-in mouse carrying the severe GCAP1 p.(E111V) variant, we show that retinal network dysfunction precedes structural degeneration. Mutant mice exhibited delayed rod photoresponses, increased light sensitivity, selective visuospatial deficits, and progressive impairment of visually evoked responses in the superior colliculus and visual cortex, demonstrating propagation of functional deficits beyond photoreceptors. Transcriptomic and ultrastructural analyses revealed early synaptic, mitochondrial and inflammatory alterations despite largely preserved retinal architecture. Acute ex vivo delivery of recombinant wild-type GCAP1 partially restored mutant rod photoresponse kinetics, indicating that these early functional deficits remain biochemically modifiable. These findings redefine severe GUCA1A-associated disease as a progressive disorder of retinal network function, identifying an early therapeutic window before structural degeneration. One-Sentence SummaryVisual function breaks down long before photoreceptors are lost, opening an early window for intervention.

neuroscience↗

bioRxiv2026

Transcranial direct current stimulation (tDCS) promotes myelin repair and plasticity in the mouse motor cortex

Cortical myelin loss and oligodendroglial dysfunction, hallmarks of numerous neurodegenerative and psychiatric disorders, compromise executive, sensory, and cognitive functions by altering circuit activity and integrity. Promoting cortical myelin repair therefore represents a critical therapeutic goal. In this frame, modulation of neuronal activity through non-invasive brain stimulation may represent a promising non-pharmacological approach to support remyelination. To address this issue, we investigated the effects of anodal transcranial direct current stimulation (A-tDCS) in a mouse model of unilateral myelin injury in the motor cortex. A-tDCS was delivered over the contralateral uninjured cortex during a bilateral motor task (locomotion), to enhance the physiological activity of interhemispheric M1-M1 projections and indirectly stimulate the lesioned cortex. When applied during the late phase of demyelination and the onset of repair, A-tDCS accelerated remyelination and increased oligodendroglial survival and maturation in the lesioned cortex, compared with unstimulated controls. Increased myelin was also detected in the directly stimulated uninjured cortex despite unchanged oligodendroglial cell numbers, suggesting de novo myelin formation or remodeling of existing internodes. These structural changes were accompanied by preservation of interhemispheric M1-M1 functional connectivity upon injury. Collectively, our findings demonstrate that A-tDCS promotes cortical myelin repair in vivo, supporting its therapeutic potential for disorders characterized by myelin damage. Notably, the observed effects of tDCS on myelin plasticity in the uninjured cortex - reported here for the first time - reveal a previously unrecognized mechanism underlying tDCS-mediated neuromodulation. HighlightsO_LIAnodal tDCS (A-tDCS) promotes remyelination in the mouse motor cortex (M1) and restores M1-M1 synchrony after demyelinating injury C_LIO_LIA-tDCS enhances oligodendroglial survival and maturation in the injured motor cortex C_LIO_LIA-tDCS induces myelin plasticity in the uninjured cortex C_LI

neuroscience↗

bioRxiv2023

Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance

Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites1. Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus, provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage2. Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and -ketoglutarate-KG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo. Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

neuroscience↗

bioRxiv2020

Neural precursor cells contribute to decision-making by tuning striatal connectivity via secretion of IGFBPL-1

The adult brain retains endogenous neural stem/precursors cells (eNPCs) in two major neurogenic niches, the subgranular zone (SGZ) in the hippocampus and the subventricular zone (SVZ). While in humans and rodents the SGZ contributes to memory functions by generating new neurons that integrate into hippocampal circuitry, the role of eNPCs of the SVZ is less clear. SVZ-eNPCs contribute to the generation of new neurons fated to the olfactory bulb (OB) in rodents but not in humans where they are thought to contribute to striatal neurogenesis as a result of tissue damage. Here, we show in mice and humans a novel non-neurogenic physiological role of adult SVZ-eNPCs in supporting cognitive functions by regulating striatal neuronal activity. We first provide evidence that GABAergic transmission between parvalbumin-expressing fast-spiking interneurons (FSIs) and medium spiny neurons (MSNs) is tuned by SVZ-eNPCs via secretion of Insulin-Like Growth Factor Binding Protein Like 1 (IGFBPL-1) that, in turn, regulates the Insulin-Like Growth Factor (IGF-1) signalling cascade. Consistently, selective ablation of SVZ-eNPCs and in vivo disruption of the IGF-signalling determine the impairment of intrastriatal coherence. A finding associated with a higher failure rate of GABAergic transmission mediated by FSIs and with striatum-related behavioural dysfunctions impairing decision making. Human validation studies revealed IGFBPL-1 expression in the SVZ and in foetal and induced-pluripotent stem cell-derived NPCs as well as a strong correlation in neurological patients between SVZ pathological damage, reduction of striatum volume and impairment of information processing speed. All in all, our results highlight a novel non-neurogenic homeostatic role exerted by SVZ-eNPCs on striatal GABAergic neurons that might contribute to cognitive processes involving decisions-making tasks.

neuroscience↗