This editorial expands on a Praxis article published by Beattie and colleagues in the trainees’ section of this journal. The authors describe an interesting case of anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, outline the clinical presentation and make suggestions on ways to approach this rare disorder. Here we provide an overview of autoimmune conditions that result in the production of autoantibodies targeting central nervous system proteins mediating autoimmune encephalitis and offer a perspective on approaches to diagnosis and treatment.

Actions of antagonists for excitatory amino-acid (EAA) receptors on extracellularly and intracellularly recorded responses of layer II/III cells to electrical stimulation of the underlying white matter were studied in a slice preparation of rat's visual cortex. Antagonists used were 2-amino-5-phosphonovalerate (APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which are selective antagonists for EAA receptors of N-methyl-D-aspartate (NMDA) and quisqualate/kainate (non-NMDA) type, respectively. In extracellular recordings, it was found that responses of almost all of the cells were suppressed by CNQX. In contrast, sensitivity to APV was different between cells with short- and long-latency responses; 81% of the former responses were not suppressed by APV, while about a half of the latter were suppressed. Excitatory postsynaptic potentials (EPSPs) evoked by white-matter stimulation were recorded intracellularly from 42 neurons. Most of polysynaptically elicited EPSPs were sensitive to APV, whereas the majority of monosynaptic EPSPs were not. CNQX almost completely suppressed EPSPs irrespective of monosynaptically or polysynaptically evoked, but in some cases slow EPSPs with low amplitude were spared. These CNQX-resistant EPSPs were elicited polysynaptically and had an anomalous voltage dependence, a characteristic of NMDA receptors. It is suggested that non-NMDA receptors contribute dominantly to first-order synaptic transmission while NMDA receptors participate substantially in second-order transmission so as to serve as a booster of outputs from visual cortex.

Stimulation of neuronal cells by the excitatory amino acid, glutamate, often leads to a rise in cytosolic free calcium concentration ([Ca2+]$sub/sub$), which can affect cell survival and differentiation. The early appearance of endogenous glutamate in the embryonic rabbit retina suggests that it may be involved in intercellular signalling during development. Thus, the effect of glutamate on the [Ca2+]$sub/sub$ of cells in the fetal and neonatal rabbit retina was examined using Ca2+ imaging techniques, which enabled the responses of large numbers of morphologically identified classes of cell to be compared directly. Ganglion cells and amacrine cells, the first retinal neurons to differentiate, showed a rise in [Ca2+]$sub/sub$ in the presence of glutamate from the earliest age studied (embryonic day 20; E20). These responses were mediated by non-NMDA (non-N-methyl-D-aspartate) receptors. NMDA stimulated ganglion cells and amacrine cells only several days later, at about E24. Moreover, whilst most, if not all, putative ganglion cells responded to NMDA, only a subset of putative amacrine cells were sensitive to NMDA throughout development. Photoreceptors, bipolar cells, horizontal cells, and Müller cells differentiate later than the ganglion cells and amacrine cells. Between E20 and birth, cells in the ventricular zone are largely the precursors of these cell types. During this period, 50–60% of ventricular cells responded to glutamate with an increase in [Ca2+]$sub/sub$, upon activation of ionotropic non-NMDA receptors. At no age studied were these ventricular cells, or their differentiated counterparts, stimulated by NMDA. After birth, most cells in the inner nuclear layer were sensitive to non-NMDA receptor agonists, but photoreceptors showed no response. Taken together, the results suggests that NMDA and non-NMDA receptors may adopt separate roles during retinal development, and that non-NMDA receptors, rather than NMDA receptors, may be involved in developmental processes in the ventricular zone.

Although it is well known that neurotransmitters mediate neuron-to-neuron communication, it is becoming clear that neurotransmitters also affect glial cells. However, knowledge of neuron-to-glial signalling is limited. In this study, we examined the effects of the glutamate agonist N-methyl-D-aspartate (NMDA) on Müller cells, the predominant glia of the retina. Our immunocytochemical studies and immunodetection by Western blotting with monoclonal antibodies specific for the NMDAR1 subunit provided evidence for the expression by human Müller cells of this essential component of NMDA receptor-channels. Under conditions in which potassium currents were blocked, NMDA-induced currents could be detected in perforated-patch recordings from cultured and freshly dissociated human Müller cells. These currents were inhibited by competitive and non-competitive blockers of NMDA receptor-channels. Extracellular magnesium reduced the NMDA-activated currents in a voltage-dependent manner. However, despite a partial block by magnesium, Müller cells remained responsive to NMDA at the resting membrane potential. Under assay conditions not blocking K+ currents, exposure of Müller cells to NMDA was associated with an MK-801 sensitive inhibition of the inward-rectifying K+ current (IK(IR)), the largest current of these glia. This inhibitory effect of NMDA appears to be mediated by an influx of calcium since the inhibition of IK(IR) was significantly reduced when calcium was removed from the bathing solution or when the Müller cells contained the calcium chelator, BAPTA. Inhibition of the Müller cell KIR channels by the neurotransmitter glutamate is likely to have significant functional consequences for the retina since these ion channels are involved in K+ homeostasis, which in turn influences neuronal excitability.

Pharmacological studies have implicated retinal opiate pathways in the visual regulation of ocular growth. However, the effects of opiate receptor subtype-specific compounds on form-deprivation myopia (FDM) are inconsistent (Seltner et al., 1997), and may be mediated by non-opiate receptors. The purpose of this study was to test whether opiate receptor-inactive (D-) enantiomers elicit the same FDM-suppressing effect as their opiate receptor-active (L-) counterparts. Since some opiates are thought to act at NMDA receptors, we also tested whether NMDA receptor agonists and antagonists influence ocular growth or FDM. We found that both L- and D- enantiomers of morphine-like compounds (dextrorphanol and levorphanol, and D- and L-naloxone) were equally effective in blocking FDM. The NMDA receptor antagonists dextromethorphan, MK801, and AP5 also suppressed FDM. A single toxic dose of NMDA, that destroys many subtypes of amacrine cells (including those that synthesize the opioid peptide enkephalin), induced myopia and ocular enlargement in ungoggled eyes, and eliminated the ability of form-deprivation to enhance ocular growth. The NR-1 subunit of the NMDA receptor was localized to a narrowly stratified, intense stratum at approximately 50% depth in the inner plexiform layer, diffusely throughout the proximal inner plexiform layer, and to many somata in the amacrine and ganglion cell layers. These observations suggest that most effects of opiate receptor ligands on FDM in the chick are mediated by non-opiate receptors, which are likely to include NMDA receptors. NMDA as an excitotoxin transiently enhances ocular growth, but thereafter disables retinal mechanisms that promote emmetropization and FDM. These observations are consistent with a prominent role for pathways utilizing NMDA receptors in FDM and ocular growth-control.