Postsynaptic GABA sub(B) Receptor Activity Regulates Excitatory Neuronal Architecture and Spatial Memory

Cognitive dysfunction is a common symptom in many neuropsychiatric disorders and directly correlates with poor patient outcomes. The majority of prolonged inhibitory signaling in the brain is mediated via GABA sub(B) receptors (GABA sub(B) Rs), but the molecular function of these receptors in cognition is ill defined. To explore the significance of GABA sub(B) Rs in neuronal activity and cognition, we created mice with enhanced postsynaptic GABA sub(B) R signaling by mutating the serine 783 in receptor R2 subunit (S783A), which decreased GABA sub(B) R degradation. Enhanced GABA sub(B) R activity reduced the expression of immediate-early gene-encoded protein Arc/Arg3.1, effectors that are critical for long-lasting memory. Intriguingly, S783A mice exhibited increased numbers of excitatory synapses and surface AMPA receptors, effects that are consistent with decreased Arc/Arg3.1 expression. These deficits in Arc/Arg3.1 and neuronal morphology lead to a deficit in spatial memory consolidation. Collectively our results suggest a novel and unappreciated role for GABA sub(B) R activity in determining excitatory neuronal architecture and spatial memory via their ability to regulate Arc/Arg3.1.