Fig. 6: Comparative pathology and MR correlates of impaired hippocampal functional connectivity in human anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and murine NMDAR antibody disease models.

A Pathophysiological mechanisms in murine NMDAR encephalitis disease model, drawn in the immunofluorescence staining of a coronal brain section from a mouse with intrathecal NR1 antibody injection of cohort 1. As expected, immunofluorescence on murine brain sections shows characteristic antibody binding of high-affinity NR1-reactive monoclonal IgG1 antibody (clone #003-102) to hippocampal neuropil. This characteristic pattern has been detected in previous works using similar human cerebrospinal fluid NMDAR autoantibodies [16]. Preferential antibody-binding to hippocampal neuropil is explained by high expression of NMDA receptors in this region [10]. Particularly, NR1-subunit of the NMDAR is widely expressed in all parts of the human hippocampal formation, including dentate gyrus, CA1-CA3, subiculum, presubiculum and entorhinal cortex [36] and similar distribution patterns are likewise seen in rodent brains with hippocampal levels of NR1 protein widely exceeding the levels of cortex, olfactory bulb, midbrain and cerebellum [37]. NR1-antibodies lead to degradation of hippocampal NMDAR in dentate gyrus and CA1-CA3. Projection fibers from entorhinal cortex (blue) are entering stratum moleculare of dentate gyrus via perforant path. Pyramidal neurons in CA3 receive intrahippocampal projection fibers from dentate gyrus (yellow) and from external fibers from medial septum and contralateral hippocampus (pink). Dysfunction of hippocampal neurons in dentate gyrus and CA3 lead to impairment in the connectivity of hippocampal circuits. B Reduced functional connectivity (significantly different area displayed based on p-values in blue-lightblue) within frontal (but not posterior) parts of the hippocampus (hippocampal functional component area displayed as z-map in red-yellow; anatomical area of dentate gyrus displayed in green) of NR1 mice compared to controls (cohort 1). CA3 (gray) is labeled according the Allen Mouse Brain Atlas (AMBA). No significant differences were seen at the middle or posterior portions of the dentate gyrus / hippocampal formation. C Reduced functional connectivity (blue) between both the left and the right hippocampus (green area) and the anterior default-mode network in NMDARE patients compared to healthy controls (original picture published in Finke et al. [6]). Ent = entorhinal cortex; NR1-ab = NR1 IgG antibodies; NMDARE = anti-NMDAR encephalitis; MS = medial septum; Hippo = contralateral hippocampus; DG = dentate gyrus; Sub = subiculum.