The function of these neuro-glial synapses is unknown, but it is hypothesised that they may signal levels of activity within neural circuits, perhaps allowing OPC to regulate their proliferation or differentiation at sites of increased activity [141,190]

The function of these neuro-glial synapses is unknown, but it is hypothesised that they may signal levels of activity within neural circuits, perhaps allowing OPC to regulate their proliferation or differentiation at sites of increased activity [141,190]. and in CC-671 OPC on a constitute lacking OPC would continue to receive glutamatergic stimulation from NMDAR [165,184,185], thus actvitity-dependent glutamate signaling could still influence OL maturation and myelination [185] (but see [186]). In contrast, Mensch et al. [183] and Etxeberria et al. [182] targeted glutamate release, rather than AMPAR expression, thus OPC in these studies could continute to receive stimulation from glutamate released by non-vesicular sources, which may CC-671 act on both AMPAR and NMDAR. The use of an inducible-conditional deletion, perhaps via a multiplex CRISPR-based knockout strategy, could help to bring further clarity to the role of AMPAR signaling in OPC maturation and myelination. Notably, OPC AMPAR are activated by vesicular release of glutamate from unmyelinated axons in white and grey matter [141,187,188,189] (Physique 1A CC-671 and Physique 2A). The function of these neuro-glial synapses is usually unknown, but it is usually hypothesised that they may signal levels of activity within neural circuits, perhaps allowing OPC to regulate their proliferation or differentiation at sites of increased activity [141,190]. In agreement with this idea, AMPAR-mediated input declines upon differentiation of OPC [191], and synaptic activity can induce Ca2+ influx into OPC via AMPAR [159,160], thus the synaptic activation of pro-differentiation Ca2+-dependent intracellular signals seems a possibility. However, recent evidence suggests a role for axon-OPC synapses in regulating proliferation but not differentiation [180]. In this work increases in the Ca2+ permeability of OPC AMPR via OPC specific expression of either non Q/R edited GluA2 subunits, or a pore lifeless GluA2 construct, promoted OPC proliferation without affecting differentiation or survival. Thus neuronal activity may influence OPC proliferation via the activation of OPC AMPAR and the subsequent activation of Ca2+-dependent signaling pathways. Interestingly, an additional strategy that reduced the proportion of Ca2+ permeable AMPAR in OPC without affecting GluA2 channel properties caused an increase in the size of the OPC populace without altering proliferation or survival [180] suggesting further complexities in the influence of AMPAR on OPC development. Contrasts between these findings, and those indicating an enhancement of OPC proliferation following AMPAR antagonism in cerebellar slice cultures [41,43] may be explained if bath applied AMPAR blockers, as used on ex vivo slices, affect additional mechanisms that impinge on OPC functions. One possibility, as highlighted previously [41], would be an effect on neuronal synapses whose inhibition would be expected to produce similar effects to that seen when neuronal activity is usually blocked pharmacologically. Of note, both TTX and the AMPAR antagonist GYKI induce a similar stimulation of OPC proliferation in cerebellar Rabbit Polyclonal to CYTL1 slice cultures [41]. Taken together there is considerable evidence that OPC AMPAR, including those recruited via neuron-OPC synapses, exert influences on OPC migration, proliferation and survival during CNS development (Physique 1A). Interestingly, a large numbers of OPC, or NG2-glia, persist in the adult CNS where they continue to receive synaptic input from neuronal circuits [reviewed by 182]. These NG2+ cells seem able to respond to this activity since, like their developmental counterparts [161], they exhibit activity-dependent and neurotransmitter receptor dependent Ca2+ transients [192]. These observations, and CC-671 morphological data showing that their processes make romantic contact with multiple neuronal and astrocyte elements, are suggestive of specialized functions within the CNS [192]. Indeed, it has been proposed that NG2+ cells might regulate glutamatergic synapses by modulating postsynaptic AMPA [193], although this idea remains controversial at this time [194]. Aside from a role in remyelination (Section 3.2) other functions for OPC/NG2-glia in the adult CNS remains an open question. Regarding differentiated OL, both iOL and mOL continue to express AMPAR (Section 3.1), and GluA4 has been detected in rodent spinal cord myelin [106] and human cortical white matter [167]. Ca2+-permeable AMPAR CC-671 made up of GluA4 may contribute to activity-dependent signaling between axons and myelin. Electrical stimulation of an ex vivo optic nerve preparation induces Ca2+ signaling in myelin that is blocked.