PP2A-dependent downregulation of GABAB receptors modulates somatostatin interneurons function and plasticity

Cortical circuits require precise inhibitory and excitatory neurotransmission to encode information and prevent pathology. Metabotropic GABA B receptors (GABA B Rs) are key inhibitory regulators in mammalian neurons. In GABAergic interneurons (INs), GABA B R activation reduces inhibition, leading to disinhibitory mechanisms. Hippocampal somatostatin-expressing (SST) INs provide feedback inhibition to distal dendrites of principal cells (PCs) and other INs. Plasticity of SST INs is well established to control hippocampal circuit function dependent on metabotropic glutamate receptors (mGluRs) and GABA B Rs. Whether GABA B Rs regulate SST INs function over longer time scales and if this influences circuit function remains unclear. We combine quantitative freeze-fracture replica immunoelectron microscopy, ex vivo electrophysiology, and pharmacology to show that GABA B R activation regulates long-term potentiation (LTP) of SST INs through protein phosphatase 2A (PP2A)-dependent loss of cell-surface GABA B R, mGluR1α receptors, and Ca v 1.2 (L-type) Ca 2+ channels. GABA B R loss in SST INs shifts hippocampal activity toward greater plasticity of long-range inputs to CA1.