Effects of Different Isotypes of Anti-NMDAR1 Autoantibodies on Cognitive Function and Neuroprotection - Project Summary High titers of anti-NMDAR1 IgG autoantibodies in brain cause anti-NMDAR1 encephalitis that exhibits psychosis, impaired memory, and many other psychiatric symptoms in addition to neurological symptoms. We found that blood circulating anti-NMDAR1 IgG autoantibodies are sufficient to impair spatial working memory (p=2.02E-08, power: 1) with a large effect size (d=2.3) in the integrity of the blood-brain barriers (BBB). Low titers of natural anti-NMDAR1 autoantibodies, predominantly IgM or IgA isotype, were reported in the blood of ~5-10% of the general human population and psychiatric patients. It is unknown whether chronic presence of these natural anti-NMDAR1 autoantibodies may impact human cognitive functions. After quantifying the levels of plasma natural anti-NMDAR1 autoantibodies in 143 Marines, we found that Marines with higher levels of natural anti-NMDAR1 autoantibodies have significantly better cognitive functions in both Continuous Performance Test (reaction time in CPT, p=0.00029) and Short Letter N-Back test (reaction time in SLNB, p=0.00091) than Marines with lower levels of the autoantibodies. Consistent with the pro-cognition, high levels of natural anti-NMDAR1 autoantibodies protect (p=0.048) from the development of TBI-associated symptoms. Anti-NMDAR1 autoantibodies had been reported to provide protections against neuronal excitotoxicity caused by excessive glutamate in neurological diseases. Therefore, it appears that blood circulating anti-NMDAR1 autoantibodies may have two opposing effects. Synaptic NMDARs are essential for cognitive function and their activation promotes neuronal survival, whereas activation of extrasynaptic NMDARs is responsible for neuronal excitotoxicity. Unlike small IgG, IgM antibodies (diameter of ~30 nm) are physically too large to enter synaptic cleft (width: 20-30 nm) to suppress synaptic NMDAR-mediated neurotransmission but are restricted to bind extrasynaptic NMDARs and therefore specifically inhibit neuronal excitotoxicity. Hence, we hypothesize that blood circulating anti-NMDAR1 IgM autoantibodies are both neuroprotective and pro-cognitive, whereas blood circulating anti-NMDAR1 IgG and IgA autoantibodies are detrimental to cognitive functions. We propose two specific aims for this 3-year R01 application. In Aim 1, we will validate pro-cognitive and neuroprotective functions of pre-existing IgM anti-NMDAR1 autoantibodies by quantifying plasma anti-NMDAR1 IgM, IgA, IgG autoantibodies, respectively, in humans. In Aim 2, we will cross-species validate pro-cognition and neuroprotection of IgM anti-NMDAR1 autoantibodies by generating mice carrying either IgM or (IgG and IgA) only anti-NMDAR1 autoantibodies. Immunogold electron microscopy will be used to validate that IgM anti- NMDAR1 autoantibodies can only bind extrasynaptic NMDAR1 but not synaptic NMDAR1 in brain. Success of the proposed studies will open up a new avenue for the development of therapeutic IgM anti-NMDAR1 autoantibodies that can promote cognitive functions and protect from neuronal excitotoxicity in many neurological diseases and psychiatric disorders including TBI, PTSD, and schizophrenia.
