DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and 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 behavior, but their etiology remains elusive. Transgenic DMSXL mice carry the DM1 mutation, show behavioral abnormalities, and express low levels of GLT1, a critical regulator of glutamate concentration in the synaptic cleft. However, the impact of glutamate homeostasis on neurotransmission in DM1 remains unknown. We confirmed reduced glutamate uptake in the DMSXL hippocampus. Patch clamp recordings in hippocampal slices revealed increased amplitude of tonic glutamate currents in DMSXL CA1 pyramidal neurons and DG granule cells, likely mediated by higher levels of ambient glutamate. Unexpectedly, extracellular GABA levels and tonic current were also elevated in DMSXL mice. Finally, we found evidence of synaptic dysfunction in DMSXL mice, suggestive of abnormal short-term plasticity, illustrated by an altered LTP time course in DG and in CA1. Synaptic dysfunction was accompanied by RNA foci accumulation in localized areas of the hippocampus and by the mis-splicing of candidate genes with relevant functions in neurotransmission. Molecular and functional changes triggered by toxic RNA may induce synaptic abnormalities in restricted brain areas that favor neuronal dysfunction.

Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes

“…We propose that impaired astrocyte arborization and polarity in DMSXL mice (comparable to that found in other mouse models of astrocyte dysfunction 24 , 68 ), may affect the ultrastructure and maturation of the synapse in vivo, in terms of astroglial coverage, synapse-to-astrocyte distance, and dendritic arborization. In this context, it will be important to investigate defects in the ultrastructural and functional interplay between astrocytes and neurons, which may contribute to the aberrant tonic currents and synaptic plasticity of DMSXL mice 69 .…”

Altered Behavioral Responses Show GABA Sensitivity in Muscleblind-Like 2-Deficient Mice: Implications for CNS Symptoms in Myotonic Dystrophy

“…Recently, it was found that DMSXL mice have elevated extracellular GABA levels and tonic currents in the hippocampus. This dysfunction coincided with RNA foci accumulation in areas of the hippocampus and by the mis-splicing of candidate genes with relevant functions in neurotransmission, one of which being Gabrg2 ( Potier et al, 2022 ). These results further support our behavioral findings of increased GABA sensitivity in Mbnl2 KO mice.…”

Neurotransmitters in Type 2 Diabetes and the Control of Systemic and Central Energy Balance

“…This process creates neuronal circuits that facilitate communication between neurons through chemical synapses. Abnormal neurotransmitter levels reflect dysregulation of brain functions that manifest as physical, psychologic, and neurodegenerative diseases [ 51 , 52 , 53 , 54 , 55 ].…”