Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6–121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10–20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage.

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 ∼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.

The function of brain oscillations remains unclear, although a role in controlling the flow of signals among anatomically connected networks has been proposed. In this Opinion article, Akam and Kullmann discuss how network oscillations might convey multiplexed information that enables a flexible reconfiguration of effective connectivity among brain areas. Mammalian brains exhibit population oscillations, the structures of which vary in time and space according to behavioural state. A proposed function of these oscillations is to control the flow of signals among anatomically connected networks. However, the nature of neural coding that may support selective communication that depends on oscillations has received relatively little attention. Here, we consider the role of multiplexing, whereby multiple information streams share a common neural substrate. We suggest that multiplexing implemented through periodic modulation of firing-rate population codes enables flexible reconfiguration of effective connectivity among brain areas.