Recently, GBR1, a seven-transmembrane domain protein with high affinity for gamma-aminobutyric acid (GABA)B receptor antagonists, was identified. Here, a GBR1-related protein, GBR2, was shown to be coexpressed with GBR1 in many brain regions and to interact with it through a short domain in the carboxyl-terminal cytoplasmic tail. Heterologously expressed GBR2 mediated inhibition of adenylyl cyclase; however, inwardly rectifying potassium channels were activated by GABAB receptor agonists only upon coexpression with GBR1 and GBR2. Thus, the interaction of these receptors appears to be crucial for important physiological effects of GABA and provides a mechanism in receptor signaling pathways that involve a heterotrimeric GTP-binding protein.

We generated mouse mutants with targeted AMPA receptor (AMPAR) GluR-B subunit alleles, functionally expressed at different levels and deficient in Q/R-site editing. All mutant lines had increased AMPAR calcium permeabilities in pyramidal neurons, and one showed elevated macroscopic conductances of these channels. The AMPAR-mediated calcium influx induced NMDA-receptor-independent long-term potentiation (LTP) in hippocampal pyramidal cell connections. Calcium-triggered neuronal death was not observed, but mutants had mild to severe neurological dysfunctions, including epilepsy and deficits in dendritic architecture. The seizure-prone phenotype correlated with an increase in the macroscopic conductance, as independently revealed by the effect of a transgene for a Q/R-site-altered GluR-B subunit. Thus, changes in GluR-B gene expression and Q/R site editing can affect critical architectural and functional aspects of excitatory principal neurons.

Objective Leucine‐rich glioma‐inactivated 1 (LGI1) encephalitis is the second most common antibody‐mediated encephalopathy, but insight into the intrathecal B‐cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. Methods We cloned, expressed, and tested antibodies from 90 antibody‐secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. Results Eighty‐four percent of the ASCs and 21% of the memory B cells encoded LGI1‐reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non–ADAM22‐competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Interpretation Our data show that the patients’ intrathecal B‐cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N‐methyl‐D‐aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405–418