PP2A-dependent internalisation of GABAB receptors in somatostatin interneurons regulates function and plasticity.

Cortical circuits rely on a precise balance of inhibitory and excitatory neurotransmission to encode information reliably and prevent pathology. Metabotropic GABAB receptors (GABABRs) are key regulators of inhibitory signalling in mammalian neurons. In GABAergic interneurons (INs), GABABR activation reduces inhibition overall, leading to disinhibitory mechanisms. In the hippocampus, somatostatin-expressing (SST) INs form a major subtype that provides feedback inhibition to the distal dendrites of principal cells (PCs) and other INs. Plasticity of SST INs is well established as a mechanism controlling hippocampal circuit function through both inhibitory and disinhibitory pathways and depends on metabotropic glutamate receptors (mGluRs) and GABABRs. However, whether activation of GABABRs induces metaplastic changes in SST INs, and how this influences circuit function and behaviour, remains unclear. Here, we combined quantitative SDS-digested freeze-fracture replica immunoelectron microscopy, ex vivo electrophysiology, in vivo behavioural testing, and pharmacological manipulation of GABABRs. We show that receptor activation directly regulates SST IN plasticity via protein phosphatase 2A (PP2A)-dependent internalisation. GABABR activation not only controls its own surface expression but also regulates membrane levels of mGluR1 and high-voltage-activated Cav1.2 (L-type) Ca2+ channels. This GABABR-dependent metaplasticity shifts circuit plasticity toward greater enhancement of long-range inputs to the CA1 region and disrupts contextual memory formation. These findings demonstrate that receptor-mediated surface dynamics in SST INs are critical for maintaining physiological neurotransmission and proper hippocampal microcircuit function.