Neuronal hibernation following hippocampal demyelination

Abstract

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.

High‐resolution diffusion tensor imaging and T2 mapping detect regional changes within the hippocampus in multiple sclerosis

“…Although all these MRI metrics are sensitive to neurodegeneration and gliosis, 48 this could maybe suggest the greater sensitivity of MD to reflect demyelination (see Table 8.2 in Chapter 8 49 that shows MD elevation in genetic animal models without myelin vs. wild type with myelin). Animal models of MS have demonstrated demyelination of the hippocampus using histology and/or other quantitative MRI methods 50–53 . Atrophy, FA, and T2 values could be further influenced by additional pathology (e.g., neuronal/axonal loss, inflammatory activity, edema, gliosis), present in some types of MS hippocampal lesions in histology 1,4 …”

Novel in vitro Experimental Approaches to Study Myelination and Remyelination in the Central Nervous System

“…Hippocampus contains many myelinated axons projecting within the hippocampus ( Arnold and Trojanowski, 1996 ), whose alterations may profoundly affect learning and memory. Hippocampal demyelination is a prominent feature of MS brain, and hippocampal atrophy correlates with cognitive decline in MS patients ( Baltan et al, 2021 ). Nevertheless, it has been shown that CA1 neurons may survive demyelination and hibernate in a state that protects the demyelinated axon, facilitating functional recovery following remyelination.…”

Structural Plasticity of the Hippocampus in Neurodegenerative Diseases

“…Particularly, as fatality is rare in the early stage of MS, there is limited information about the acute effects of hippocampal demyelination on spine pathologies in patients with MS. However, there was no change in the spine density of demyelinated hippocampi of cuprizone-diet fed mice, except for an increase in the proportion of mushroom-shaped spines [ 298 ]. This increase was nullified with the withdrawal of the cuprizone diet and subsequent remyelination.…”