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.
Highlights
The cellular complexity of the central nervous system (CNS) presents formidable challenges for investigating disease mechanisms
Demyelination silences CA1 neuronal activity and abolishes Long-term potentiation (LTP) Six weeks of cuprizone-mediated hippocampal demyelination diminishes the capacity of CA1 neurons to spontaneously fire in vivo and reduces CA1 synaptic responses in vitro [32]
The present study investigated how 12 weeks of hippocampal demyelination, as well as subsequent remyelination, alters CA1 neuronal function and LTP in hippocampal slices
Summary
The cellular complexity of the central nervous system (CNS) presents formidable challenges for investigating disease mechanisms. This is especially the case for multiple sclerosis (MS), which is a CNS disease characterized by demyelination of both white matter and gray matter. Upon removal of cuprizone from the diet for six weeks, ~ 60% of hippocampal myelin is replaced by remyelination and memory/learning is restored [9]. This supports the hypothesis that neuronal and synaptic function are altered by demyelination and restored by remyelination
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