A specific GABAergic synapse onto oligodendrocyte precursors does not regulate cortical oligodendrogenesis

Abstract

In the brain, neurons establish bona fide synapses onto oligodendrocyte precursor cells (OPCs), but the function of these neuron-glia synapses remains unresolved. A leading hypothesis suggests that these synapses regulate OPC proliferation and differentiation. However, a causal link between synaptic activity and OPC cellular dynamics is still missing. In the developing somatosensory cortex, OPCs receive a major type of synapse from GABAergic interneurons that is mediated by postsynaptic γ2-containing GABA receptors. Here we genetically silenced these receptors in OPCs during the critical period of cortical oligodendrogenesis. We found that the inactivation of γ2-mediated synapses does not impact OPC proliferation and differentiation or the propensity of OPCs to myelinate their presynaptic interneurons. However, this inactivation causes a progressive and specific depletion of the OPC pool that lacks γ2-mediated synaptic activity without affecting the oligodendrocyte production. Our results show that, during cortical development, the γ2-mediated interneuron-to-OPC synapses do not play a role in oligodendrogenesis and suggest that these synapses finely tune OPC self-maintenance capacity. They also open the interesting possibility that a particular synaptic signaling onto OPCs plays a specific role in OPC function according to the neurotransmitter released, the identity of presynaptic neurons or the postsynaptic receptors involved.

Oligodendroglia-lineage cells in brain plasticity, homeostasis and psychiatric disorders

“…In support of this idea, interruption of thalamacortical projections onto primary somatosensory barrel cortex by whisker deflection altered proliferation, differentiation, survival [32] and distribution [54] of NG2-glia around the barrels. Recently, inactivation of 2-mediated synapses received from2 GABAergic neurons on NG2-glia has been shown to cause a progressive loss of the NG2-glia pool without affecting proliferation, differentiation or myelination [55], indicating a role for these synapses in the tight regulation of NG2-glial cell numbers in the adult CNS. Yet, considerably less is known about whether and how NG2-glia influence neuronal function.…”

Glutamate versus GABA in neuron–oligodendroglia communication

“…However, whether Ca 2+ increases induced by GABA A R activation occur in physiological conditions and affect OPC function is unclear. Two‐photon Ca 2+ imaging of OPCs recently revealed a high level of spontaneous intracellular Ca 2+ activity that increases with neuronal stimulation in acute slices of the immature somatosensory cortex (Balia, Benamer, & Angulo, ). However, these signals persist in the absence of GABA A R‐mediated synapses containing γ2 subunits, suggesting that they do not involve synaptic mechanisms (Balia et al, ).…”

“…Two‐photon Ca 2+ imaging of OPCs recently revealed a high level of spontaneous intracellular Ca 2+ activity that increases with neuronal stimulation in acute slices of the immature somatosensory cortex (Balia, Benamer, & Angulo, ). However, these signals persist in the absence of GABA A R‐mediated synapses containing γ2 subunits, suggesting that they do not involve synaptic mechanisms (Balia et al, ). Moreover, the presence of type A potassium channels in OPCs limits possible synaptic Ca 2+ responses in these cells (Sun, Matthews, Nicolas, Schoch, & Dietrich, ).…”

“…One of the leading hypotheses concerning the function of the GABAergic signaling in oligodendroglia is that GABA plays a central role in controlling OPC proliferation and differentiation. However, a number of contradictory results have been reported when considering either a specific role of GABAergic synaptic signaling or a more general role of GABA in OPC function (Balia et al, ; Hamilton et al, ; Zonouzi et al, ). In a model of perinatal hypoxia, Zonouzi et al () demonstrated an important dysregulation of GABA signaling in both neurons and OPCs during postnatal development.…”

“…In addition, although the pharmacological or genetic tools used in these studies affect GABA signaling, they are not exclusive for synaptic GABA A Rs and could affect OL lineage cells at any maturation stage. To assess a more specific role of GABA A R‐mediated synapses of OPCs, we recently inactivated γ2‐GABA A R synapses by deleting the γ2 subunit in these progenitors (Balia et al, ). We observed a robust decrease in the frequency of postsynaptic currents suggesting that, among the two major interneuron–OPC synapses described so far (Orduz et al, ), those containing γ2‐GABA A Rs are specifically and completely inactivated in these mice.…”