PP2A-dependent downregulation of GABAB receptors modulates somatostatin interneurons function and plasticity
Abstract
Cortical circuits require precise inhibitory and excitatory neurotransmission to encode information and prevent pathology. Metabotropic GABAB receptors (GABABRs) are key inhibitory regulators in mammalian neurons. In GABAergic interneurons (INs), GABABR 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 GABABRs. Whether GABABRs 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 GABABR activation regulates long-term potentiation (LTP) of SST INs through protein phosphatase 2A (PP2A)-dependent loss of cell-surface GABABR, mGluR1α receptors, and Cav1.2 (L-type) Ca2+ channels. GABABR loss in SST INs shifts hippocampal activity toward greater plasticity of long-range inputs to CA1.
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BibTeX
@article{sethumadhavan2026pp2adependent,
title = {{PP2A-dependent downregulation of GABAB receptors modulates somatostatin interneurons function and plasticity}},
author = {Nithya Sethumadhavan and Max A. Wilson and Anna Sumera and Desiree Loreth and Rita M. Loureiro and Imre Vida and Akos Kulik and Sam A. Booker},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117878},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03261-X},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PP2A-dependent downregulation of GABAB receptors modulates somatostatin interneurons function and plasticity
AU - Nithya Sethumadhavan
AU - Max A. Wilson
AU - Anna Sumera
AU - Desiree Loreth
AU - Rita M. Loureiro
AU - Imre Vida
AU - Akos Kulik
AU - Sam A. Booker
PY - 2026
DA - 2026/10/27
JO - iScience
DO - 10.1016/j.isci.2026.117878
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03261-X
AB - Cortical circuits require precise inhibitory and excitatory neurotransmission to encode information and prevent pathology. Metabotropic GABAB receptors (GABABRs) are key inhibitory regulators in mammalian neurons. In GABAergic interneurons (INs), GABABR 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 GABABRs. Whether GABABRs 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 GABABR activation regulates long-term potentiation (LTP) of SST INs through protein phosphatase 2A (PP2A)-dependent loss of cell-surface GABABR, mGluR1α receptors, and Cav1.2 (L-type) Ca2+ channels. GABABR loss in SST INs shifts hippocampal activity toward greater plasticity of long-range inputs to CA1.
SN - 2589-0042
ER -