Neuronal hibernation following hippocampal demyelination

Acta Neuropathologica Communications

Ricky Chan¹  Harsha D. Battapady²  Anthony M. Chomyk²  Bruce D. Trapp²  Grahame J. Kidd²  Ranjan Dutta²  Safdar S. Jawaid³  Selva Baltan⁴  Jacqueline Chen⁵ 

[1] Cleveland Institute for Computational Biology, 44106, Cleveland, OH, USA;Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, 44195, Cleveland, OH, USA;Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, 44195, Cleveland, OH, USA;Department of Pediatrics, School of Medicine, Case Western Reserve University, 44106, Cleveland, OH, USA;Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, 44106, Cleveland, OH, USA;Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, 44195, Cleveland, OH, USA;Department of Perioperative Medicine, Oregon Health and Science University, 97239, Portland, OR, USA;Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, 44195, Cleveland, OH, USA;Imaging Institute, Cleveland Clinic, 44195, Cleveland, OH, USA;

关键词: Hippocampal demyelination;    Long-term potentiation (LTP);    Dendritic spines;    Transcript profiling;   

DOI  :  10.1186/s40478-021-01130-9

来源: Springer

【 摘 要 】

Cognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains and hippocampal atrophy correlates with cognitive decline in MS patients. Cellular and molecular mechanisms responsible for neuronal dysfunction in demyelinated hippocampi are not fully understood. Here we investigate a mouse model of hippocampal demyelination where twelve weeks of treatment with the oligodendrocyte toxin, cuprizone, demyelinates over 90% of the hippocampus and causes decreased memory/learning. Long-term potentiation (LTP) of hippocampal CA1 pyramidal neurons is considered to be a major cellular readout of learning and memory in the mammalian brain. In acute slices, we establish that hippocampal demyelination abolishes LTP and excitatory post-synaptic potentials of CA1 neurons, while pre-synaptic function of Schaeffer collateral fibers is preserved. Demyelination also reduced Ca2+-mediated firing of hippocampal neurons in vivo. Using three-dimensional electron microscopy, we investigated the number, shape (mushroom, stubby, thin), and post-synaptic densities (PSDs) of dendritic spines that facilitate LTP. Hippocampal demyelination did not alter the number of dendritic spines. Surprisingly, dendritic spines appeared to be more mature in demyelinated hippocampi, with a significant increase in mushroom-shaped spines, more perforated PSDs, and more astrocyte participation in the tripartite synapse. RNA sequencing experiments identified 400 altered transcripts in demyelinated hippocampi. Gene transcripts that regulate myelination, synaptic signaling, astrocyte function, and innate immunity were altered in demyelinated hippocampi. Hippocampal remyelination rescued synaptic transmission, LTP, and the majority of gene transcript changes. We establish that CA1 neurons projecting demyelinated axons silence their dendritic spines and hibernate in a state that may protect the demyelinated axon and facilitates functional recovery following remyelination.

【 授权许可】

CC BY