The synaptic blocker botulinum toxin A decreases the density and complexity of oligodendrocyte precursor cells in the adult mouse hippocampus.

Irene Chacon‐De‐La‐Rocha,Matteo Caleo,Diego Gomez‐Nicola,Arthur M Butt,Gemma L Fryatt,Laura Restani,Andrea D Rivera

doi:10.1002/jnr.24856

Abstract

Oligodendrocyte progenitor cells (OPCs) are responsible for generating oligodendrocytes, the myelinating cells of the CNS. Life-long myelination is promoted by neuronal activity and is essential for neural network plasticity and learning. OPCs are known to contact synapses and it is proposed that neuronal synaptic activity in turn regulates their behavior. To examine this in the adult, we performed unilateral injection of the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of adult mice. We confirm BoNT/A cleaves SNAP-25 in the CA1 are of the hippocampus, which has been proven to block neurotransmission. Notably, BoNT/A significantly decreased OPC density and caused their shrinkage, as determined by immunolabeling for the OPC marker NG2. Furthermore, BoNT/A resulted in an overall decrease in the number of OPC processes, as well as a decrease in their lengths and branching frequency. These data indicate that synaptic activity is important for maintaining adult OPC numbers and cellular integrity, which is relevant to pathophysiological scenarios characterized by dysregulation of synaptic activity, such as age-related cognitive decline, Multiple Sclerosis and Alzheimer's disease.

Highlights

Oligodendrocyte precursor cells (OPCs) are a significant population of cells in the adult brain with the fundamental function of life-long generation of oligodendrocytes, which is required to myelinate new connections formed in response to new life experiences and to replace myelin lost through natural ‘wear and tear’ and disease [1,2,3]
We investigated the effects of prolonged synaptic silencing on adult Oligodendrocyte progenitor cells (OPCs), by local injection of botulinum toxin A (BoNT/A) into the mouse hippocampal CA1 region, which has been shown to produce a sustained blockade of synaptic transmission via cleavage of the synaptic protein SNAP-25 21,24,25
We show that injection of botulinum neurotoxin A (BoNT/A) into the hippocampus, which cleaves SNAP-25 and silences synaptic signalling 24, results in a decrease in OPC density and a decrease in OPC morphological complexity

Summary

Introduction

Oligodendrocyte precursor cells (OPCs) are a significant population of cells in the adult brain with the fundamental function of life-long generation of oligodendrocytes, which is required to myelinate new connections formed in response to new life experiences and to replace myelin lost through natural ‘wear and tear’ and disease [1,2,3]. Several lines of evidence indicate neuronal synaptic activity regulates OPC proliferation and differentiation [12,13,14,15]. Optogenetic studies have shown that neuronal activity stimulates OPC proliferation and differentiation in the cortex 16. Motor learning has been shown to drive OPC differentiation and myelination of newly formed neuronal connections, and failure to generate new oligodendrocytes impairs learning ability [17,18]. It is proposed that decreased synaptic activity may result in disruption of OPC regenerative capacity in neurodegenerative diseases, such as Multiple Sclerosis (MS) and Alzheimer’s disease (AD) 19,20

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