A new class of severe but treatable autoimmune encephalitides is associated with serum and CSF autoantibodies to cell surface receptors that are thought to cause disease by disrupting the normal function of their target protein. Consistent with disruption of the major neurotransmission pathways and thus circuit malfunction in the central nervous system, symptoms of these newly characterized diseases are severe and include psychosis, memory loss, confusion, seizures, and autonomic instability normal function. The majority of symptoms resolve with aggressive immunosuppresive therapy. The best characterized of these encephalitides is associated with antibodies to ionotropic glutamate receptors, N-methyl-D-aspartate receptor (NMDAR) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). NMDAR and AMPAR autoantibodies cross-link the cognate synaptic receptors on the surface of cultured neurons and result in a selective internalization of the target without disruption of any other synaptic component or injury to neurons. In a passive transfer animal model, chronic perfusion of NMDAR antibodies into the cerebrospinal fluid (CSF) of mice also decreases NMDA receptors after 14 days, which results in anhedonia and diminished spatial memory. Consistent with the reversible course of disease, the effects of NMDAR and AMPAR autoantibodies can be reversed in both in vivo and in vitro model systems. These mechanisms may underlie the neurological and psychiatric manifestations of these forms of autoimmune encephalitis, and account for recovery of many patients with immune therapy aimed at lowering antibody titer. Patients with antibodies to the metabotropic gamma-aminobutyric acid receptor type B (GABAB receptor) develop severe intractable seizures, but little is known about the underlying pathophysiological mechanisms. Deletion mapping and expression in heterologous cells showed that patient anti-GABAB antibodies bind to alternatively spliced Sushi domains present in the presynaptically localized GABAB1a isoform. In contrast to patient anti-NMDAR antibodies, GABAB autoantibodies did not result in a decrease in surface GABAB receptors or their internalization. Treating neurons with GABABR autoantibodies for two hours blocked the activation of GABAB receptors by baclofen in a titer-dependent manner. Autoantibody-bound GABABRs are still signaling competent, because baclofen block was circumvented by directly activating GABAB2 with a selective agonist, CGP7930. Patient GABAB receptor autoantibodies are selective GABAB1 antagonists that may contribute to seizures by interfering with GABA-mediated inhibition. Brain penetrant GABAB2 agonists may be useful to treat intractable seizures in anti-GABAB receptor encephalitis patients.