Long-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory1. The classical form of LTP relies on N-methyl-D-aspartate receptors (NMDARs), and it has emerged that astroglia can regulate their activation through Ca2+-dependent release of the NMDAR co-agonist D-serine2-4. Release of D-serine from glia enables LTP in cultures5 and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus4. However, Ca2+ elevations in astroglia can also release other signalling molecules, most prominently glutamate6-8, Adenosine-5′-triphosphate9, and Tumor-Necrosis-Factor-α10,11 whereas neurons themselves can synthesise and supply D-serine12,13. Furthermore, loading an astrocyte with exogenous Ca2+ buffers does not suppress LTP in hippocampal area CA114-16, and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned17,18. The involvement of glia in LTP induction thus remains controversial. Here we show that clamping internal Ca2+ in individual CA1 astrocytes blocks LTP induction at nearby excitatory synapses by reducing the occupancy of the NMDAR co-agonist sites. This LTP blockade can be reversed by exogenous D-serine or glycine whereas depletion of D-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. We thus demonstrate that Ca2+-dependent release of D-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses occurring nearby.

Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies BOLD functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptors (mGluR5) on astrocytes, evoking Ca2+ release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knock-out of the IP3 receptors that release Ca2+ from stores does not affect neurovascular coupling. We now show that buffering astrocyte Ca2+ inhibits neuronally-evoked capillary dilation, that astrocyte [Ca2+]i is raised not by release from stores but by entry through ATP-gated channels, and that Ca2+ generates arachidonic acid via phospholipase D2 and diacylglycerol kinase rather than phospholipase A2. In contrast, dilation of arterioles depends on NMDA receptor activation and Ca2+-dependent NO generation by interneurons. These results reveal that different signalling cascades regulate cerebral blood flow at the capillary and arteriole levels.

Fast excitatory synapses are generally thought to act as private communication channels between presynaptic and postsynaptic neurons. Some recent findings, however, suggest that glutamate may diffuse out of the synaptic cleft and bind to several subtypes of receptors, either in the perisynaptic membrane or at neighboring synapses. It is not known whether activation of these receptors can occur in response to the release of a single vesicle of glutamate. Here we estimate the spatiotemporal profile of glutamate in the extrasynaptic space after vesicle exocytosis, guided by detailed ultrastructural measurements of the CA1 neuropil in the adult rat. We argue that the vicinity of the synapse can be treated as an isotropic porous medium, in which diffusion is determined by the extracellular volume fraction and the tortuosity factor, and develop novel stereological methods to estimate these parameters. We also estimate the spatial separation between synapses, to ask whether glutamate released at one synapse can activate NMDA and other high-affinity receptors at a neighboring synapse. Kinetic simulations of extrasynaptic glutamate uptake show that transporters rapidly reduce the free concentration of transmitter. Exocytosis of a single vesicle is, however, sufficient to bind to high-affinity receptors situated in the immediate perisynaptic space. The distance separating a typical synapse from its nearest neighbor is approximately 465 nm. Whether glutamate can reach a sufficient concentration to activate NMDA receptors at this distance depends critically on the diffusion coefficient in the extracellular space. If diffusion is much slower than in free aqueous solution, NMDA receptors could mediate crosstalk between neighboring synapses.

Long-term potentiation (LTP), which approximates Hebb's postulate of associative learning, typically requires depolarization-dependent glutamate receptors of the NMDA (N-methyl-Daspartate) subtype. However, in some neurons, LTP depends instead on calcium-permeable AMPA-type receptors. This is paradoxical because intracellular polyamines block such receptors during depolarization. We report that LTP at synapses on hippocampal interneurons mediating feedback inhibition is "anti-Hebbian": It is induced by presynaptic activity but prevented by postsynaptic depolarization. Anti-Hebbian LTP may occur in interneurons that are silent during periods of intense pyramidal cell firing, such as sharp waves, and lead to their altered activation during theta activity.Associative N-methyl-D-aspartate receptor (NMDAR)-dependent LTP is induced by coincident activity in afferent pathways sufficient to depolarize postsynaptic neurons (1). However, the voltage dependence of Ca 2+ -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) is opposite to that of NMDARs (2, 3). Because CP-AMPARs are blocked by cytoplasmic polyamines upon depolarization (4, 5), maximal Ca 2+ influx occurs when the membrane potential is relatively negative. LTP dependent on CP-AMPARs occurs in interneurons of the spinal cord and amygdala (6, 7), but its postsynaptic voltage dependence has not been explored. In hippocampal interneurons, CP-AMPARs have been implicated in long-term depression (8-10), and contribute to synaptic Ca 2+ transients, especially in the stratum oriens/alveus (11). Many interneurons in the oriens/alveus also show NMDAR-independent LTP (12). We therefore looked for associative LTP in these cells, while recording with the gramicidin perforated patch technique to preserve intracellular polyamines (13).Stimulation of pyramidal cell axon collaterals in the alveus evoked monosynaptic excitatory postsynaptic potentials (EPSPs) subthreshold for evoking action potentials. After recording a baseline, we paired high-frequency burst (HFB) stimulation (five pulses at 100 Hz, repeated 20 times) with stimulation of a second, supra-threshold, alveus pathway. "In-phase" associative pairing (phase difference ΔΦ = 0°) failed to elicit associative LTP in either pathway (n = 7; Fig. 1, A Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts two weak pathways, and then delivered HFBs to both pathways antiphase (ΔΦ = 180°). This evoked a persistent increase in EPSP initial slope in one or both pathways in all cells (n = 7; Fig. 1, C and D). LTP was elicited even when HFB stimuli were delivered to only one weak pathway (n = 7; Fig. 1, E and F). Thus, LTP at excitatory synapses on interneurons in the oriens/alveus is prevented by associative pairing, in direct contrast to NMDAR-dependent LTP (1).Can direct manipulation of the postsynaptic membrane potential similarly gate LTP induction? We delivered HFBs to one pathway coinciding with the trough (somatic voltage: −90 mV) of an imposed 4-Hz sinusoidal ...