Altered EEG markers of synaptic plasticity in a human model of NMDA receptor deficiency: anti-NMDA receptor encephalitis

Abstract

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-methyl-D-aspartate receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of non-rapid eye movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.

Sleep spindles across youth affected by schizophrenia or anti-N-methyl-D-aspartate-receptor encephalitis

“…Sleep data from three patient groups were gathered for the purpose of this study. Screening procedures and characteristics of patient groups have previously been published (22,32,33). Allnight EEG, demographic, and clinical data from individuals with COS (N = 17, 16.0 ± 3.6 years, 70.6% female), EOS (N = 11, 16.4 ± 1.4 years, 36.4% female), NMDARE (N = 8, 13.3 ± 4.5 years, 75.0% female), and 36 age-and sex-matched HC were pooled in this project.…”

“…Epoch-specific sleep staging and artifact rejection were available from previous analyses (22,32,33). Sleep stages were scored based on standard criteria by a sleep expert and either validated by a second sleep expert (COS, EOS, HC) or by one rater only to reduce inter-rater variability (NMDARE) (38).…”

“…A rare form of autoimmune encephalitis, anti-NMDAR encephalitis (NMDARE), is induced by autoantibodies that target the NMDAR leading to a functional deficit (20). The symptomatology of NMDARE and SZ also greatly overlap, often presenting with sleep and cognitive disturbances and culminating with a range of psychotic symptoms (21,22). This has encouraged research in the context of the glutamate hypothesis of SZ (23)(24)(25)(26)(27)(28).…”