DM1 transgenic mice exhibit abnormal neurotransmitter homeostasis and synaptic plasticity in association with RNA mis-splicing in the hippocampus. - Archive ouverte HAL Access content directly
Poster Communications Year : 2023

DM1 transgenic mice exhibit abnormal neurotransmitter homeostasis and synaptic plasticity in association with RNA mis-splicing in the hippocampus.

Abstract

Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disease mediated by a toxic gain of function of mutant RNAs. The neuropsychological manifestations affect multiple domains of cognition and behaviour, but their aetiology remains elusive. Transgenic DMSXL mice carry the human DM1 mutation and show relevant behavioural abnormalities (including altered exploratory behaviour and anhedonia) and express reduced levels of GLT1, a critical regulator of glutamate homeostasis in the brain. However, the impact of glutamate homeostasis dysfunction on neurotransmission in DM1 remains unknown. In the present study, we show an in vivo reduced glutamate uptake in the DMSXL hippocampus compared to wildtype mice, but extracellular glutamate levels sampled in the dorsal hippocampus using zero-flow quantitative microdialysis were unaltered. Patch clamp recordings of CA1 pyramidal neurons and DG granule cells in hippocampal slices from DMSXL mice revealed an increased tonic excitation, likely mediated by higher levels of ambient glutamate at the vicinity of extrasynaptic NMDA receptors. We also found an unexpected elevated extracellular GABA level in DMSXL mice associated with an increase in tonic inhibition and a higher GABA release. Finally, we found evidence of abnormal short-term plasticity in the DG and CA1 area, suggestive of synaptic dysfunction in DMSXL mice. Synaptic dysfunction was accompanied by the accumulation of RNA foci that are more abundant and larger in the DG than in CA1 area, and by the mis-splicing of candidate genes with relevant functions in amino acidergic neurotransmission (ion channels, neurotransmitter receptors and synaptic proteins, as well as proteins involved in neuronal vesicle trafficking). Taken together, molecular and functional changes triggered by the accumulation of toxic RNA may induce synaptic abnormalities in restricted brain areas of the brain, causing neuronal dysfunction.
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Dates and versions

hal-04005556 , version 1 (26-02-2023)

Identifiers

  • HAL Id : hal-04005556 , version 1

Cite

B Potier, Louison Lallemant, Sandrine Parrot, Aline Huguet-Lachon, Geneviève Gourdon, et al.. DM1 transgenic mice exhibit abnormal neurotransmitter homeostasis and synaptic plasticity in association with RNA mis-splicing in the hippocampus.. NeuroFrance, May 2023, Lyon, France. ⟨hal-04005556⟩
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