NMDA-receptor antibodies alter cortical microcircuit dynamics

Area of Science:

• Neuroscience
• Immunology
• Computational Biology

Background:

• Autoimmune encephalitis is associated with N-methyl-D-aspartate receptor antibodies (NMDAR-Abs).
• NMDAR-Abs are known to cause diverse electroencephalogram (EEG) abnormalities, including seizures.
• The precise mechanisms by which NMDAR-Abs disrupt neuronal function and lead to paroxysmal EEG events remain unclear.

Purpose of the Study:

• To investigate the circuit-level mechanisms underlying EEG abnormalities in NMDAR-antibody encephalitis.
• To identify key synaptic parameters contributing to paroxysmal EEG activity in patients.
• To model the impact of NMDAR-Abs on cortical microcircuitry and brain dynamics.

Main Methods:

• Utilized local field potential recordings in a mouse model of NMDAR-Ab encephalitis.
• Developed and validated a dynamic causal model of NMDAR-Ab effects on cortical microcircuits.
• Identified critical synaptic parameters by analyzing EEG paroxysms in pediatric patients.

Main Results:

• NMDAR-Abs alter intrinsic cortical connections and neuronal population dynamics.
• These alterations change the spectral composition of spontaneous EEG activity.
• NMDAR-Ab-induced changes sensitize microcircuits to EEG paroxysms, unlike in control models.

Conclusions:

• NMDAR-Abs disrupt cortical microcircuitry, leading to altered EEG spectral composition.
• Specific synaptic parameter changes, tolerated in controls, trigger overt EEG paroxysms in the NMDAR-Ab model.
• Findings provide mechanistic insights into circuit dysfunction in NMDAR-Ab encephalitis.