Background A poorly understood facet of lupus is its neurological component, known as Neuropsychiatric Systemic Lupus Erythematosus (NPSLE). Patients with NPSLE display severe cognitive impairment, particularly in the spatial domain. We have studied a mouse model of NPSLE in which animals carry a lupus antibody (termed DNRAb) that binds DNA and the GluN2A and GluN2B subunits of the N-methyl-D aspartate receptor (NMDAR).
Methods Female mice (Balb/c, C57) are immunized with either a lupus-inducing antigen (DNRAb+) or a control antigen (DNRAb–). A month later, the blood-brain barrier is abrogated to allow antibody entry to the hippocampus. We investigate spatial cognition with the object-place memory (OPM) task and the neural substrate with tetrode recordings in the CA1 region of the hippocampus. Neural data are analyzed via spike sorting (Spike2) to reveal place cell properties of CA1 neurons, as well as power spectral densities of network oscillations (Matlab, Chronux).
Results A discrimination ratio reveals that DNRAb+ mice examine the moved object significantly less than controls during OPM, indicating impaired spatial memory. The neural data show abnormal place cell properties in DNRAb+ mice, such as expanded place field size, reduced stability, and lower spatial information when compared to DNRAb– mice. Bayesian path reconstruction analysis reveals that DNRAb+ place cells have significantly higher error compared to the DNRAb– group. Moreover, we find significantly altered co-modulation of theta-gamma oscillations when the mice examine the objects during OPM.
Conclusions Our studies reveal that the CA1 ensemble encodes critical aspects of the OPM task through place cell dynamics and theta-gamma coupling. The disruptions of these processes caused by DNRAbs may explain the abnormal spatial encoding that occurs in NPSLE. Our data offer a neural substrate for bioelectronic therapies aimed to alleviate NPSLE-related cognitive impairment.
Acknowledgments The studies are funded by grants from NIH (P01-AI102852, P01-AI073693) and DOD (2019 Impact Award) to PTH.
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