Summary The generation of precise synaptic connections between developing neurons is critical to the formation of functional neural circuits. Astrocyte-secreted glypican 4 induces formation of active excitatory synapses by recruiting AMPA glutamate receptors to the postsynaptic cell surface. We now identify the molecular mechanism of how glypican 4 exerts its effect. Glypican 4 induces release of the AMPA receptor clustering factor neuronal pentraxin 1 from presynaptic terminals by signaling through presynaptic protein tyrosine phosphatase receptor δ. Pentraxin then accumulates AMPA receptors on the postsynaptic terminal forming functional synapses. Our findings reveal a signaling pathway which regulates synaptic activity during central nervous system development and demonstrates a role for astrocytes as organizers of active synaptic connections, by coordinating both pre and post synaptic neurons. As mutations in glypicans are associated with neurological disorders such as autism and schizophrenia this signaling cascade offers new avenues to modulate synaptic function in disease.

Autoantibodies targeting the GABAA receptor (GABAAR) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient derived monoclonal antibodies (mAbs). We cloned and recombinantly produced five affinity-maturated GABAAR IgG1 mAbs from cerebrospinal fluid cells, which bound to various epitopes involving α1 and γ2 receptor subunits, with variable binding strength and partial competition. mAbs selectively reduced GABAergic currents in neuronal cultures without causing receptor internalization. Cerebroventricular infusion of GABAAR mAbs and Fab fragments into rodents induced a severe phenotype with catatonia, seizures and increased mortality, reminiscent of encephalitis patients’ symptoms. Our results prove direct functional effects of autoantibodies on GABAARs and provide an animal model for GABAAR encephalitis. They further provide the scientific rationale for clinical treatments using antibody depletion and pave the way for future antibody-selective immunotherapies.

Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody‐mediated synaptic dysfunction. Cerebrospinal fluid–derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline‐configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose‐ and time‐dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771–776

Autoantibodies against central nervous system proteins are increasingly being recognized in association with neurological disorders. Although a growing number of neural autoantibodies have been identified, a causal link between specific autoantibodies and disease symptoms remains unclear, as most studies utilize patient derived cerebrospinal fluid (CSF) containing mixtures of autoantibodies. This raises questions concerning mechanism of action and which autoantibodies truly contribute to disease progression. To address this issue, monoclonal autoantibodies were isolated from a young girl with a range of neurological symptoms, some of which reacted with specific GABA A receptor subunits, α1-and α1γ2-subunits, which in this study, we have characterized in detail using a combination of cellular imaging and electrophysiological techniques. These studies in neurons from wild-type mice (C57BL/6J) (RRID:IMSR_JAX:000664) of mixed-sex revealed that the α1 and α1ɣ2 subunit-specific antibodies have differential effects on the GABA A receptor. Namely, the α1-antibody was found to directly affect GABA A receptor function on a short time scale that diminished GABA currents, leading to increased network excitability. On longer time scales those antibodies also triggered a redistribution of the GABA A receptor away from synapses. In contrast, the α1γ2-antibody had no direct effect on GABA A receptor function and could possibly mediate its effect through other actors of the immune system. Taken together these data highlight the complexity underlying autoimmune disorders and show that antibodies can exert their effect through many mechanisms within the same disease.