Abstract
Neurons form bona fide synapses with oligodendrocyte precursor cells (OPCs), but the circuit context of these neuron to OPC synapses remains incompletely understood. Using monosynaptically-restricted rabies virus tracing of OPC afferents, we identified extensive afferent synaptic inputs to OPCs residing in secondary motor cortex, corpus callosum, and primary somatosensory cortex of adult mice. These inputs primarily arise from functionally-interconnecting cortical areas and thalamic nuclei, illustrating that OPCs have strikingly comprehensive synaptic access to brain-wide projection networks. Quantification of these inputs revealed excitatory and inhibitory components that are consistent in number across brain regions and stable in barrel cortex despite whisker trimming-induced sensory deprivation.
Highlights
Excitatory and inhibitory synapses between neurons and oligodendrocyte precursor cells (OPCs) are well-established and the ultrastructural and electrophysiological features of these ‘axon->glial’ synapses have been investigated in slice preparations, generally by evoking potentials in local fiber bundles (Ziskin et al, 2007; De Biase et al, 2010; Kukley et al, 2007; Lundgaard et al, 2013)
Development and validation of retrograde monosynaptic OPC tracing strategy Owing to the lack of viral tools to achieve specific transgene expression in OPCs, we employed a transgenic strategy by crossing Pdgfra::CreER mice (Kang et al, 2010), which permit OPC-specific Cre recombinase expression, with a Cre-inducible RABVgp4/TVA mouse (Takatoh et al, 2013)
EnvA’s highly specific interaction with the TVA receptor ensures restriction of primarily-transduced cells – hereafter named starter cells – to the Pdgfra+ OPC cell population. Because these OPCs express rabies gp4, virions can be assembled within these starter cells and spread retrogradely across single synaptic connections to presynaptic input neurons; because these input neurons do not express gp4, there is no additional spread of virus beyond these monosynaptic connections (Figure 1A) (Wickersham et al, 2007)
Summary
Excitatory and inhibitory synapses between neurons and OPCs are well-established and the ultrastructural and electrophysiological features of these ‘axon->glial’ synapses have been investigated in slice preparations, generally by evoking potentials in local fiber bundles (Ziskin et al, 2007; De Biase et al, 2010; Kukley et al, 2007; Lundgaard et al, 2013). Recent evidence has demonstrated that neuronal activity robustly regulates OPC proliferation, oligodendrogenesis, and myelination in both juvenile and adult rodents (Gibson et al, 2014; Mitew et al, 2018; Hughes et al, 2018) and influences axon selection during developmental myelination in zebrafish (Mensch et al, 2015; Hines et al, 2015) These activity-regulated responses of oligodendroglial cells have been shown to confer adaptive changes in motor function (Gibson et al, 2014), are necessary for some forms of motor learning (McKenzie et al, 2014; Xiao et al, 2016) and contribute to cognitive behavioral functions such as attention and short-term memory (Geraghty et al, 2019). We find brain-wide, functionally-interconnected inputs to OPCs and that the degree of this connectivity is stable across brain regions and is maintained despite whisker trimming-induced sensory deprivation in barrel cortex at the timepoint examined
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