Biology subjects

Montheil, A.

Publications and source records attributed to Montheil, A..

3 recordsLinked to original sources

bioRxiv2025

Early and transient increase in cortical pyramidal cell excitability and delayed alteration of evoked synaptic transmission and t-SNARE proteins content in the hippocampus and neocortex of neonatal and juvenile STXBP1 heterozygous mice

De novo mutations in the STXBP1 gene leads to the haploinsufficiency of Munc18.1 protein in patient, and represent one of the major causes of neurodevelopmental disorders including developmental epileptic and non-epileptic encephalopathies. Given the fundamental role of this protein in vesicular exocytosis, most electrophysiological studies have focused on the impact of this haploinsufficiency on synaptic transmission, and much less on intrinsic neuronal properties. Furthermore, the possibility that the electrophysiological consequences may be dependent on the developmental stage has not yet been investigated. Here, we analyze using acute brain slices from neonatal and juvenile STXBP1 heterozygous mice the intrinsic properties as well as spontaneous and evoked glutamatergic and GABAergic synaptic transmission in pyramidal cells located in the CA1 region of the hippocampus and in layers II/III of the motor cortex. We show that Munc18.1 deficiency has different electrophysiological consequences in neonatal (postnatal days, PND 4-7) and juvenile mice (PND30-35). The deficit of Munc18.1 leads to an increase in the intrinsic excitability of hippocampal and motor cortical pyramidal cells in neonates while in juveniles, it is evoked synaptic transmission that is affected, with a greater sensitivity of glutamatergic synapses than of GABAergic synapses in response to high-frequency electrical stimulation. However spontaneous ongoing synaptic activity mediated by glutamate and GABA receptors was unaffected at both stages of development. In addition, we performed western blot analysis and observed that Munc18.1 deficiency in STXBP1 heterozygous mice is associated with decreased t-SNARE proteins expression levels in the hippocampus and neocortex of juvenile but not neonatal mice. Therefore, Munc18.1 deficiency has multiple electrophysiological and biochemical consequences, which depend on the developmental stage. These data suggest also that an alteration in the function of some ion channels is one of the first electrophysiological consequences of the deficit of Munc18.1 and we suggest that the decrease in t-SNARE proteins expression could contribute to the normalization of pyramidal cells firing properties in juvenile.

neuroscience↗

bioRxiv2019

Characterization and rescue by oxytocin of an atypical thermo-sensory reactivity in neonatal mice lacking the autism-associated gene Magel2.

Atypical responses to sensory stimuli are considered as a core aspect and early life marker of autism spectrum disorders (ASD). Although recent findings performed in mouse ASD genetic models report sensory deficits, these were explored exclusively during juvenile or adult period. Whether sensory dysfunctions might be present at the early life stage and rescued by therapeutic strategy are fairly uninvestigated. Here we identified that neonatal mice lacking the autism-associated gene Magel2 fail to react to cool sensory stimuli, while autonomic thermoregulatory function is active. This neonatal deficit was mimicked in control neonates by chemogenetic inactivation of oxytocin neurons. Importantly, intranasal administration of oxytocin was able to rescue the phenotype and brain Erk signaling impairment in mutants. This preclinical study establishes for the first-time early life impairments in thermosensory integration and shows the therapeutic potential benefits of intranasal oxytocin treatment on neonatal atypical sensory reactivity.

neuroscience↗

bioRxiv2018

Morphofunctional deficits in the cerebral cortex of NeuroD2 mutant mice are associated with autism/schizophrenia-like behaviors

We identified seven families associating NEUROD2 pathogenic mutations with ASD and intellectual disability. To get insight into the pathophysiological mechanisms, we analyzed cortical development in Neurod2 KO mice. Cortical projection neurons (CPNs) over-migrated during embryogenesis, inducing abnormal thickness and laminar positioning of cortical layers. At juvenile ages, dendritic spine turnover and intrinsic excitability were increased in L5 CPNs. Differentially expressed genes in Neurod2 KO mice were enriched for voltage-gated ion channels, and the human orthologs of these genes were strongly associated with ASD. Furthermore, adult Neurod2 KO mice exhibited core ASD-like behavioral abnormalities. Finally, by generating Neurod2 conditional mutant mice we demonstrate that forebrain excitatory neuron-specific Neurod2 deletion recapitulates cellular and behavioral ASD phenotypes found in full KO mice. Our findings demonstrate crucial roles for Neurod2 in cortical development and function, whose alterations likely account for ASD and related symptoms in the newly defined NEUROD2 mutation syndrome.

neuroscience↗