Preventive and Therapeutic Autoantibodies Protect against Neuronal Excitotoxicity

High titers of anti-NMDAR1 IgG autoantibodies were found in the brains of patients with anti-NMDAR1 encephalitis that exhibits psychosis, impaired memory, and many other psychiatric symptoms in addition to neurological symptoms. Low titers of blood circulating anti-NMDAR1 IgG autoantibodies are sufficient to robustly impair spatial working memory in mice with intact blood-brain barriers (BBB). On the other hand, anti-NMDAR1 autoantibodies were reported to protect against neuronal excitotoxicity caused by excessive glutamate in neurological diseases. Activation of extrasynaptic NMDARs is responsible for neuronal excitotoxicity, whereas activation of synaptic NMDARs within the synaptic cleft is pro-survival and essential for NMDAR-mediated neurotransmission. Unlike small IgG, IgM antibodies are large and pentameric (diameter of ~30 nm). It is plausible that IgM anti-NMDAR1 autoantibodies may be restricted to bind extrasynaptic NMDARs and thereby specifically inhibit neuronal excitotoxicity, but physically too large to enter the synaptic cleft (width: 20-30 nm) to suppress synaptic NMDAR-mediated neurotransmission in modulation of cognitive function and neuronal pro-survival signaling. Hence, 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 function. Investigation of anti-NMDAR1 IgM autoantibodies may open up a new avenue for the development of long-lasting preventive and therapeutic IgM anti-NMDAR1 autoantibodies that protect from neuronal excitotoxicity in many neurological diseases and psychiatric disorders.