Patient-Derived Anti-NMDAR Antibody Disinhibits Cortical Neuronal Networks through Dysfunction of Inhibitory Neuron Output.

Anti-NMDA receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder associated with autoantibodies against NMDARs, which cause a variety of symptoms from prominent psychiatric and cognitive manifestations to seizures and autonomic instability. Previous studies mainly focused on hippocampal effects of these autoantibodies, helping to explain mechanistic causes for cognitive impairment. However, antibodies' effects on higher cortical network function, where they could contribute to psychosis and/or seizures, have not been explored in detail until now. Here, we employed a patient-derived monoclonal antibody targeting the NR1 subunit of NMDAR and tested its effects on in vitro cultures of rodent cortical neurons, using imaging and electrophysiological techniques. We report that this hNR1 antibody drives cortical networks to a hyperexcitable state and disrupts mechanisms stabilizing network activity such as Npas4 signaling. Network hyperactivity is in part a result of a reduced synaptic output of inhibitory neurons, as indicated by a decreased inhibitory drive and levels of presynaptic inhibitory proteins, specifically in inhibitory-to-excitatory neuron synapses. Importantly, on a single-cell level hNR1 antibody selectively impairs NMDAR-mediated currents and synaptic transmission of cortical inhibitory neurons, yet has no effect on excitatory neurons, which contrasts with its effects on hippocampal neurons. Together, these findings provide a novel, cortex-specific mechanism of antibody-induced neuronal hyperexcitability, highlighting regional specificity underlying the pathology of autoimmune encephalitis.SIGNIFICANCE STATEMENT It is increasingly appreciated that the inadvertent activation of the immune system within CNS can underlie pathogenesis of neuropsychiatric disorders. Although the exact mechanisms remain elusive, autoantibodies derived from patients with autoimmune encephalitis pose a unique tool to study pathogenesis of neuropsychiatric states. Our analysis reveals that autoantibody against the NMDA receptor (NMDAR) has a distinct mechanism of action in the cortex, where it impairs function of inhibitory neurons leading to increased cortical network excitability, in contrast to previously described hippocampal synaptic mechanisms of information encoding, highlighting brain regional specificity. Notably, similar mechanism of NMDAR-mediated inhibitory hypofunction leading to cortical disinhibition has been suggested to underlie pathology of schizophrenia, hence our data provide new evidence for common mechanisms underlying neuropsychiatric disorders.

Neural Entrainment to the Beat: The "Missing-Pulse" Phenomenon.

Most humans have a near-automatic inclination to tap, clap, or move to the beat of music. The capacity to extract a periodic beat from a complex musical segment is remarkable, as it requires abstraction from the temporal structure of the stimulus. It has been suggested that nonlinear interactions in neural networks result in cortical oscillations at the beat frequency, and that such entrained oscillations give rise to the percept of a beat or a pulse. Here we tested this neural resonance theory using MEG recordings as female and male individuals listened to 30 s sequences of complex syncopated drumbeats designed so that they contain no net energy at the pulse frequency when measured using linear analysis. We analyzed the spectrum of the neural activity while listening and compared it to the modulation spectrum of the stimuli. We found enhanced neural response in the auditory cortex at the pulse frequency. We also showed phase locking at the times of the missing pulse, even though the pulse was absent from the stimulus itself. Moreover, the strength of this pulse response correlated with individuals' speed in finding the pulse of these stimuli, as tested in a follow-up session. These findings demonstrate that neural activity at the pulse frequency in the auditory cortex is internally generated rather than stimulus-driven. The current results are both consistent with neural resonance theory and with models based on nonlinear response of the brain to rhythmic stimuli. The results thus help narrow the search for valid models of beat perception.SIGNIFICANCE STATEMENT Humans perceive music as having a regular pulse marking equally spaced points in time, within which musical notes are temporally organized. Neural resonance theory (NRT) provides a theoretical model explaining how an internal periodic representation of a pulse may emerge through nonlinear coupling between oscillating neural systems. After testing key falsifiable predictions of NRT using MEG recordings, we demonstrate the emergence of neural oscillations at the pulse frequency, which can be related to pulse perception. These findings rule out alternative explanations for neural entrainment and provide evidence linking neural synchronization to the perception of pulse, a widely debated topic in recent years.