Summary GABA B receptor ( GABA B R ) autoantibodies have been detected in the serum of immunotherapy‐responsive patients with autoimmune encephalitis. This study aimed to investigate the effect of immunoglobulin G (IgG) from a patient with GABA B R antibodies on primary neuronal cultures and acute slices of entorhinal cortex. Primary hippocampal neuronal cultures were incubated with serum immunoglobulin from patients with GABA B R or AMPA receptor ( AMPAR ) antibodies for up to 72 h to investigate their effect on receptor surface expression. Whole‐cell patch‐clamp recordings from layer III pyramidal cells of the medial entorhinal cortex were used to examine the effect on neuronal activity. GABA B R surface expression was unaltered by incubation with GABA B R antibodies. By contrast, after 24 h application of AMPAR antibodies, AMPAR s were undetectable. However, acute application of GABA B R IgG decreased both the duration of network UP states and the spike rate of pyramidal cells in the entorhinal cortex. GABA B R antibodies do not appear to affect GABA B R s by internalization but rather reduce excitability on the medial temporal lobe networks. This unusual mechanism of action may be exploited in rational drug development strategies.