A defining feature of glial cells has been their inability to generate action potentials. We now show that there are two distinct types of morphologically identical oligodendrocyte precursor glial cell (OPC) in situ in rat CNS white matter. One type expresses voltage-gated sodium and potassium channels, generates action potentials when depolarized, and senses its environment by receiving excitatory and inhibitory synaptic input from axons. The other type lacks action potentials and synaptic input. We show that when OPCs suffer glutamate-mediated damage, as occurs in cerebral palsy, stroke and spinal cord injury, the action potential generating OPCs are preferentially damaged because they express more glutamate receptors and in ischaemia receive increased spontaneous glutamatergic synaptic input. These data challenge the idea that only neurons generate action potentials in the CNS, and imply that the development of therapies for demyelinating disorders will require defining which OPC type can perform remyelination.Oligodendrocyte precursor glia, which express1 the proteoglycan NG2, transform into myelinating oligodendrocytes during development2, but are also present in the adult CNS3 where they comprise ∼5% of the cells and are the main proliferating cell type4,5. Damage to oligodendrocyte precursors, leading to reduced myelination, contributes to mental and physical impairment in periventricular leukomalacia (pre-or perinatal white matter injury leading to cerebral palsy)6. Adult OPCs may form new myelinating oligodendrocytes in multiple sclerosis and spinal cord injury7-12, and OPC transplants could serve as a basis for therapeutic remyelination13. However, the functions of OPCs are poorly understood: they may simply become oligodendrocytes in normal development and constitute a reservoir of cells which replace damaged myelin in the adult CNS, but they might also differentiate into other cell types and thus have some stem cell characteristics14. Understanding the diversity of NG2-expressing OPCs is crucial for understanding normal brain function, for appreciating the diversity of the brain's progenitor cell population, and for developing therapeutic strategies to treat demyelinating diseases. Results Identification of oligodendrocyte precursor gliaIn the cerebellum of postnatal day 7 (P7) rats, cells expressing NG2 constitute 14.8 ± 1.2% (n=1850 cells) of the cells present in the white matter (Fig. 1a). Essentially all of these cells (93 ± 2%, excluding perivascular NG2 cells15) also labelled for the oligodendrocyte transcription factor Olig2 (Fig. 1b-d Fig. 1e-h). In some experiments, more rapid identification of NG2-expressing OPCs was attained by labelling the living slice with an antibody to an extracellular epitope of NG2, which decorated the surface of the OPCs, allowing subsequent whole-cell clamping (Fig 1i-k). For both identification methods, OPCs fell into two distinct electrophysiological classes. Two classes of oligodendrocyte precursor gliaOne class of OPCs (which we call I Na cells) exhibi...

BackgroundCannabinoids have deleterious effects on prefrontal cortex (PFC)-mediated functions and multiple evidences link the endogenous cannabinoid (endocannabinoid) system, cannabis use and schizophrenia, a disease in which PFC functions are altered. Nonetheless, the molecular composition and the physiological functions of the endocannabinoid system in the PFC are unknown.Methodology/Principal FindingsHere, using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers V/VI of the mouse prelimbic area of the PFC: presynaptic cannabinoid CB1 receptors (CB1R) faced postsynaptic mGluR5 while diacylglycerol lipase α (DGL-α), the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol (2-AG) was expressed in the same dendritic processes as mGluR5. Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents. Prolonged synaptic stimulation at 10Hz induced a profound long-term depression (LTD) of layers V/VI excitatory inputs. The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic mGluR5, phospholipase C and a rise in postsynaptic Ca2+ as predicted from the localization of the different components of the endocannabinoid system. Blocking the degradation of 2-AG (with URB 602) but not of anandamide (with URB 597) converted subthreshold tetanus to LTD-inducing ones. Moreover, inhibiting the synthesis of 2-AG with Tetrahydrolipstatin, blocked endocannabinoid-mediated LTD. All together, our data show that 2-AG mediates LTD at these synapses.Conclusions/SignificanceOur data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the PFC. Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of PFC-related pathologies.

Until recently, the study of plasticity of neural circuits focused almost exclusively on potentiation and depression at excitatory synapses on principal cells. Other elements in the neural circuitry, such as inhibitory synapses on principal cells and the synapses recruiting interneurons, were assumed to be relatively inflexible, as befits a role of inhibition in maintaining stable levels and accurate timing of neuronal activity. It is now evident that inhibition is highly plastic, with multiple underlying cellular mechanisms. This Review considers these recent developments, focusing mainly on functional and structural changes in GABAergic inhibition of principal cells and long-term plasticity of glutamateric recruitment of inhibitory interneurons in the mammalian forebrain. A major challenge is to identify the adaptive roles of these different forms of plasticity, taking into account the roles of inhibition in the regulation of excitability, generation of population oscillations, and precise timing of neuronal firing.

Non-technical summary In the central nervous system, electrical signals passing along nerve cells are speeded by cells called oligodendrocytes, which wrap the nerve cells with a fatty layer called myelin. This layer is important for rapid information processing, and is often lost in disease, causing mental or physical impairment in multiple sclerosis, stroke, cerebral palsy and spinal cord injury. The myelin speeds the information flow in two ways, by decreasing the capacitance of the nerve cell and by increasing its membrane resistance, but little is known about the latter aspect of myelin function. By recording electrically from oligodendrocytes and imaging their morphology we characterised the geometry and, for the first time, the resistance of myelin in the brain. This revealed differences between the properties of oligodendrocytes in two brain areas and established that the resistance of myelin is sufficiently high to prevent significant slowing of the nerve electrical signal by current leakage through the myelin.Abstract Despite the textbook description that oligodendrocytes 'insulate' axons, the resistivity of the oligodendrocyte internodal membrane is unknown, and it is unknown how the electrical properties differ for oligodendrocytes which myelinate different numbers of axons or are located in different brain areas. We used whole-cell patch-clamping and dye-fill morphology to characterize the electrical properties of oligodendrocytes in the corpus callosum and the white matter of the cerebellum. At postnatal day 12, oligodendrocytes in the corpus callosum myelinated ∼10 axons, while oligodendrocytes in the cerebellum myelinated ∼7 axons. Internode lengths were shorter in the corpus callosum than in cerebellum, while the somata diameters of corpus callosal and cerebellar oligodendrocytes were similar. By correlating the conductance of the oligodendrocytes with the number and length of the internodes they made, we estimated the conductance of each internodal process and the conductivity per unit area of the oligodendrocyte internodal membrane. The derived resistance of one internodal process was ∼1.5 G in corpus callosal oligodendrocytes and ∼0.6 G in cerebellar oligodendrocytes. The specific conductance (depending on the assumptions made) was 0.63-5.5 pS μm −2 for corpus callosal oligodendrocytes and 0.28-5.0 pS μm −2 for cerebellar oligodendrocytes. These values were used, in a computational model of action potential propagation in a myelinated axon, to assess the effect of the oligodendrocyte conductance and anatomical parameters on the speed of action potential propagation. The measured oligodendrocyte membrane conductivity did Y. Bakiri and R. Káradóttir made an equal contribution. not significantly lower the action potential speed by short circuiting the myelin capacitance. Differences in axon diameter, number of myelin wraps and internode length predict that, other factors being equal, the conduction speed for cerebellar axons will be twice that for corpus callosal axons.

Damage to oligodendrocytes caused by glutamate release contributes to mental or physical handicap in periventricular leukomalacia, spinal cord injury, multiple sclerosis, and stroke, and has been attributed to activation of AMPA/kainate receptors. However, glutamate also activates unusual NMDA receptors in oligodendrocytes, which can generate an ion influx even at the resting potential in a physiological [Mg2+]. Here, we show that the clinically licensed NMDA receptor antagonist memantine blocks oligodendrocyte NMDA receptors at concentrations achieved therapeutically. Simulated ischaemia released glutamate which activated NMDA receptors, as well as AMPA/kainate receptors, on mature and precursor oligodendrocytes. Although blocking AMPA/kainate receptors alone during ischaemia had no effect, combining memantine with an AMPA/kainate receptor blocker, or applying the NMDA blocker MK-801 alone, improved recovery of the action potential in myelinated axons after the ischaemia. These data suggest NMDA receptor blockers as a potentially useful treatment for some white matter diseases and define conditions under which these blockers may be useful therapeutically. Our results highlight the importance of developing new antagonists selective for oligodendrocyte NMDA receptors based on their difference in subunit structure from most neuronal NMDA receptors.

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Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca2+ influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

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