Investigations in animal models of anti-NMDAR encephalitis

Abstract

[eng] BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neuronal antibody-mediated disease that associates with prominent neuropsychiatric symptoms and predominantly affects women of childbearing age. Animal models of this disease have enabled the demonstration that patients’ antibodies are pathogenic as they bind to NMDARs and cause their internalization, resulting in a decrease of synaptic levels of these receptors, impairment of synaptic plasticity, memory deficits, and depressive-like and psychotic-like behaviors. These antibodies are class G immunoglobulins (IgG); thus, they can be transferred across the placenta in pregnant patients with anti-NMDAR encephalitis and potentially be detrimental for the fetus/newborn. On the other hand, novel therapeutic strategies to accelerate patients’ recovery are of interest.

OBJECTIVES: 1) Report the effects of anti-NMDAR encephalitis in pregnant patients and their babies, 2) develop an animal model of placental transfer of IgG antibodies from patients with anti-NMDAR encephalitis to determine their potential pathogenic effects in the fetus and offspring, 3) investigate whether treatment with a neonatal Fc receptor (FcRn) inhibitor prevents the placental transfer of patients’ IgG and abrogates the antibody-mediated alterations in the previously developed mouse model, and 4) study the potential therapeutic use of a positive allosteric modulator (PAM) of NMDAR (i.e., SGE-301) in a reported mouse model of cerebroventricular infusion of patients’ cerebrospinal fluid (CSF) antibodies.

CONCLUSIONS: My studies have contributed to gain insight into the outcome of babies from pregnant patients with anti-NMDAR encephalitis and to unravel the antibody-mediated synaptic alterations underlying the transient developmental and behavioral impairment using a mouse model of placental transfer of patients’ IgG. Overall, these findings have provided potential therapeutic strategies in antibody-mediated diseases of the CNS during pregnancy (i.e., FcRn inhibitor) or in an adult mouse model of anti-NMDAR encephalitis (SGE-301).