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.
