EFFECTS OF PRENATAL EXPOSURE TO PATIENT-DERIVED NMDA RECEPTOR AUTOANTIBODIES ON THE DEVELOPING MOUSE STRIATUM

Anti-NMDA receptor (NMDAR) encephalitis is associated with the presence of autoantibodies against the NMDA receptor NR1 subunit which can result in psychiatric symptoms as well as cognitive and motor impairments. These autoantibodies can arise in adulthood but also during pregnancy where they have been shown to affect the developing foetal brain and are implicated in neurodevelopmental disorders including autism and learning disabilities. However, to what extent specific developing brain circuits are sensitive to NR1 antibodies is largely unknown.
The aim of our study is to explore how early exposure to patient-specific autoantibodies against the NR1 subunit affects developing neuronal circuits of the mouse striatum, a brain region involved in motor and cognitive control. We performed in utero intraventricular injections of patient-derived NR1 or control immunoglobulins (IgGs) at embryonic day E14.5 and investigated the effect on developing striatum during early postnatal stages through both patch-clamp recordings, morphological analysis and behavioural testing. Our data show that prenatal exposure to NR1 IgGs induces a change in intrinsic properties as well as reduced NMDA currents of striatal neurons at early postnatal stages. We also find changes in glutamatergic transmission at cortico-striatal synaptic connections as demonstrated by a reduced NMDA/AMPA ratio. These cellular effects of in utero injected NR1 IgGs are also reflected in altered neonatal and adult mouse behaviour and are rescuable by early treatment with glutamate receptor allosteric modulators. In conclusion, our findings show that in utero exposure to patient-derived NR1-IgGs can result in prolonged cellular and circuit changes in striatum.