A putative functional role for oligodendrocytes in mood regulation

Altered glial structure and function is implicated in several major mental illnesses and increasing evidence specifically links changes in oligodendrocytes with disrupted mood regulation. Low density and reduced expression of oligodendrocyte-specific gene transcripts in postmortem human subjects points toward decreased oligodendrocyte function in most of the major mental illnesses. Similar features are observed in rodent models of stress-induced depressive-like phenotypes, such as the unpredictable chronic mild stress and chronic corticosterone exposure, suggesting an effect downstream from stress. However, whether oligodendrocyte changes are a causal component of psychiatric phenotypes is not known. Traditional views that identify oligodendrocytes solely as nonfunctional support cells are being challenged, and recent studies suggest a more dynamic role for oligodendrocytes in neuronal functioning than previously considered, with the region adjacent to the node of Ranvier (i.e., paranode) considered a critical region of glial–neuronal interaction. Here, we briefly review the current knowledge regarding oligodendrocyte disruptions in psychiatric disorders and related animal models, with a focus on major depression. We then highlight several rodent studies, which suggest that alterations in oligodendrocyte structure and function can produce behavioral changes that are informative of mood regulatory mechanisms. Together, these studies suggest a model, whereby impaired oligodendrocyte and possibly paranode structure and function can impact neural circuitry, leading to downstream effects related to emotionality in rodents, and potentially to mood regulation in human psychiatric disorders

Modulation of extracellular glutamate concentration in rat brain slices by cystine-glutamate exchange

The role of cystine-glutamate exchange in controlling the extracellular glutamate concentration in the central nervous system was examined by whole-cell clamping neurons in rat brain slices, and using their glutamate receptors as sensors of extracellular glutamate concentration.Applying cystine to cerebellar slices generated a membrane current in Purkinje cells which was abolished by glutamate receptor blockers. Similar cystine-evoked currents were seen in pyramidal cells of frontal cortex slices.Control experiments on non-N-methyl-D-aspartate (non-NMDA) receptors in enzymatically isolated Purkinje cells showed that cystine did not produce a current in slice Purkinje cells by directly activating glutamate receptors, nor by potentiating the action of background levels of glutamate on receptors. Experiments on isolated salamander Müller cells showed that cystine did not block Na+-dependent GLAST glutamate transporters (homologous to the transporters in the Bergmann glia ensheathing the Purkinje cells), nor did it block the current produced by EAAT4 and EAAC1 glutamate transporters in Purkinje cells. Thus the cystine-evoked current in Purkinje cells is not due to a rise in extracellular glutamate concentration caused by block of Na+-dependent uptake.The dependence of cystine-evoked current on cystine concentration in slice Purkinje cells could be fitted by a Michaelis-Menten relation with a Km of 250 μM. The Km predicted from this for cystine activating glutamate efflux is less than 140 μM, because of the non-linear dependence on glutamate concentration of the Purkinje cell current. The current evoked by 1 mM cystine was little affected by removal of extracellular chloride or addition of 1 mM furosemide (frusemide), but was potentiated by 1 mM 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS).These data suggest that external cystine generates a current in slice Purkinje cells by activating cystine-glutamate exchange in cells of the slice, releasing glutamate which activates non-NMDA receptors in the Purkinje cell membrane

Mechanisms underlying presynaptic facilitatory effect of cyclothiazide at the calyx of Held of juvenile rats

Excitatory postsynaptic currents (EPSCs) were recorded using the whole-cell patch-clamp technique at the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) in auditory brainstem slices from juvenile rats.Bath application of cyclothiazide (CTZ, 100 μm) significantly increased the amplitude of EPSCs mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Cyclothiazide increased the magnitude of paired-pulse depression of both AMPA-EPSCs (intervals, 50 and 500 ms) and NMDA-EPSCs (interval, 20 ms). In low Ca2+, high Mg2+ solution, CTZ decreased the number of failures and increased the mean amplitude of AMPA-EPSCs more than three-fold.Presynaptic Ca2+ currents and K+ currents were directly recorded from the calyceal nerve terminals. These currents were attenuated by CTZ in a reversible manner. The magnitude of inhibition of presynaptic K+ currents by CTZ (100 μm) was comparable to that by 5 μm 4-aminopyridine (4-AP). Both CTZ and 4-AP slowed the repolarizing phase of presynaptic action potentials.The inhibitory effects of CTZ on presynaptic ion channels were mimicked by a solution having reduced Ca2+ concentration and 5 μm 4-AP. This solution facilitated EPSCs, but the magnitude of facilitation was significantly less than that caused by CTZ.In the presence of tetrodotoxin (TTX), CTZ increased the mean frequency of miniature EPSCs three-fold. CTZ prolonged their decay time but had no effect on their amplitude. The facilitatory effect of CTZ on the miniature frequency was neither blocked by a protein kinase C inhibitor nor occluded by phorbol ester, suggesting that a distinct mechanism underlies the effect of CTZ.We conclude that CTZ facilitates transmitter release through suppression of presynaptic potassium conductance and stimulation of exocytotic machinery downstream of Ca2+ influx

Modulation of the glycine response by Ca2+-permeable AMPA receptors in rat spinal neurones

In acutely isolated rat sacral dorsal commisural nucleus (SDCN) neurones, application of kainate (KA) reversibly potentiated glycine-evoked Cl− currents (IGly) in a concentration-dependent manner.The cellular events underlying the interaction between non-NMDA receptors and glycine receptors were studied by using nystatin-perforated patch and cell-attached single-channel recording modes.The action of KA was not accompanied by a shift in the reversal potential for IGly. In dose-response curves, KA potentiated IGly without significantly changing glycine binding affinity.GYKI 52466 blocked while NS-102 had no effect on the KA-induced potentiation of IGly.The potentiation was reduced when KA was applied in a Ca2+-free extracellular solution or in the presence of BAPTA AM, and was independent of the activation of voltage-dependent Ca2+ channels.Pretreatment with KN-62, a selective Ca2+-calmodulin-dependent protein kinase II (CaMKII) inhibitor, abolished the action of KA. Inhibition of calcineurin converted the KA-induced potentiation to a sustained one.Single-channel recordings revealed that KA decreased the mean closing time of glycine-gated single-channel activity, resulting in an increase in the probability of channel opening.It is proposed that Ca2+ entry through AMPA receptors modulates the glycine receptor function via coactivation of CaMKII and calcineurin in SDCN neurones. This interaction may provide a new postsynaptic mechanism for control of inhibitory synaptic signalling and represent one of the important regulatory mechanisms of spinal nociception

Developmental profiles of glutamate receptors and synaptic transmission at a single synapse in the mouse auditory brainstem

Using whole-cell recordings from presynaptic terminals and postsynaptic principal neurons in the mouse medial nucleus of the trapezoid body (MNTB), we have characterized properties of the calyx of Held synapse during the first three postnatal weeks. We observed that evoked excitatory postsynaptic currents (EPSCs) mediated by NMDA receptors (NMDAR) increased until postnatal day 11/12 (P11/12) after which they declined to very low or undetectable levels at P16. Meanwhile, EPSCs mediated by AMPA receptors (AMPAR) showed an approximate three-fold increase in amplitude. These changes were paralleled by NMDAR and AMPAR currents evoked by exogenous NMDA and kainate to MNTB neurons except that whole-cell kainate currents remained constant after P7/8 while AMPAR-EPSCs continued to increase. We found that the decay time constant τ for NMDAR-EPSCs and AMPAR-EPSCs declined by about 30 % and 70 %, respectively. Analyses of NMDAR-EPSCs with subunit-specific pharmacological agents including ifenprodil, N,N,N′,N′-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN), zinc and Mg2+ revealed subtle developmental changes in subunit composition. As maturation progressed, this synapse displayed a reduction in the number of presynaptic spike failures and the extent of synaptic depression in response to trains of stimuli (50–300 Hz) while the recovery rate from depression accelerated. These results demonstrate profound changes in the size and kinetics of postsynaptic glutamate receptors and in the spike-firing capability of presynaptic terminals at the calyx of Held-MNTB synapse during early development. We suggest that these concurrent presynaptic and postsynaptic adaptations represent important steps for synapse consolidation and refinement and ultimately for the development of fast high-fidelity transmission at this synapse

Synchronisation ofneurotransmitter release during postnatal development in a calyceal presynaptic terminal of rat

Mechanisms contributing to the synchronisation of transmitter release during development were studied in synapses of the medial nucleus of the trapezoid body (MNTB) using patch recording and Ca2+ imaging techniques in a rat brainstem slice preparation.Excitatory postsynaptic currents (EPSCs) were generated in an all-or-none manner at immature synapses (postnatal days earlier than P6). Many delayed miniature EPSC (mEPSC)-like currents followed EPSCs at immature synapses, while observations of delayed mEPSC-like currents were rare at mature synapses (later than P9).At immature synapses bath application of either ω-conotoxin GVIA or ω-agatoxin-IVA reduced EPSCs (both to 40% of control), and Ca2+ currents in the presynaptic terminal (both to 70% of control). The frequency of delayed mEPSC-like currents was reduced by ω-conotoxin GVIA, but not by ω-agatoxin IVA.At immature synapses delayed mEPSC-like currents were rare after incubation of the slice with extrinsic Ca2+ buffers (EGTA AM).At mature synapses many mEPSC-like currents followed evoked EPSCs after partial block of Ca2+ channels by bath application of a low concentration of Cd2+ (3 μm) or ω-agatoxin IVA (50 nm) but not by low [Ca2+]o (0.5-1 mm).Ca2+ transients induced by action potentials in presynaptic terminals were monitored by adding a high concentration of fura-2 (200 μm) to the pipette. Their decay time course was slower at immature presynaptic terminals than at mature terminals. Both the Ca2+ extrusion rate and the endogenous Ca2+ binding capacity were estimated to be smaller at immature terminals than at mature terminals.These results suggest that the maturation of synaptic transmission in MNTB progresses with the capacity for Ca2+ clearance from the presynaptic terminal. The possible importance of developmental increases in both Ca2+ clearance capacity and Ca2+ currents is discussed in relation to the synchronisation of transmitter release