Biology subjects

Becq, H.

Publications and source records attributed to Becq, H..

2 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↗

bioRxiv2020

A KCNQ2 variant causing Early Onset Epileptic Encephalopathy increases spontaneous network-driven activity and excitability of pyramidal cells in the layer II/III and V of the motor cortex during a limited period of development

De novo missense variants in the KCNQ2 gene encoding the Kv7.2 subunit of the voltage-gated potassium Kv7/M channel are the main cause of Developmental and Epileptic Encephalopathy (DEE). KCNQ2 related-DEE is characterized by pharmaco-resistant neonatal seizures associated with a developmental delay. While seizures usually resolve some weeks or months after birth, cognitive/behavioral deficits persist. To better understand the cellular mechanisms underlying KCNQ2-associated network dysfunction and their progression over time, we investigated in vivo, using local field potential recordings of freely moving animals, and ex-vivo in layers II/III and V of motor cortical slices, using patch-clamp recordings, the electrophysiological properties of pyramidal cells from a heterozygous knock-in (KI) mouse model carrying the p.T274M pathogenic variant during neonatal, post-weaning and juvenile developmental stages. We found that KI mice displayed spontaneous seizures preferentially at post-weaning rather than at juvenile stages. At the cellular level, the variant led to a reduction in M current density/chord conductance and to an increase in neuronal excitability. These alterations were observed already during the neonatal period in pyramidal cells of layers II / III and during post-weaning stage in pyramidal cells of layer V. Moreover there was an increase in the frequency of spontaneous network driven events mediated by GABA receptors in the layers II/III suggesting that the excitability of some interneurons was also increased. However, all these alterations were time limited and no more observed in layers II/III and V of juvenile mice. At this stage, M-current density and neuronal excitability were not different from the measurements made in juvenile wild-type mice. Thus our data indicate that the action of the variant on neuronal activity is developmentally regulated and that some cellular mechanisms leading to the recovery of Kv7/M channels function took place during brain maturation of KI mice. These results raise the possibility that the age related seizure remission observed in KCNQ2-related DEE patient results also from a time limited alteration of Kv7 channels activity and neuronal excitability.

neuroscience↗