mTORC1 function in hippocampal parvalbumin interneurons: regulation of firing and long-term potentiation of intrinsic excitability but not long-term contextual fear memory and context discrimination.

Publisher: BioMed Central Country of Publication: England NLM ID: 101468876 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-6606 (Electronic) Linking ISSN: 17566606 NLM ISO Abbreviation: Mol Brain Subsets: MEDLINE

Original Publication: London : BioMed Central

CA1 Region, Hippocampal*/metabolism ; Fear*/physiology ; Hippocampus*/metabolism ; Interneurons*/metabolism ; Long-Term Potentiation*/physiology ; Mechanistic Target of Rapamycin Complex 1*/metabolism ; Memory*/physiology ; Parvalbumins*/metabolism; Animals ; Mice ; Synapses/metabolism

Hippocampal CA1 parvalbumin-expressing interneurons (PV INs) play a central role in controlling principal cell activity and orchestrating network oscillations. PV INs receive excitatory inputs from CA3 Schaffer collaterals and local CA1 pyramidal cells, and they provide perisomatic inhibition. Schaffer collateral excitatory synapses onto PV INs express Hebbian and anti-Hebbian types of long-term potentiation (LTP), as well as elicit LTP of intrinsic excitability (LTP IE ). LTP IE requires the activation of type 5 metabotropic glutamate receptors (mGluR5) and is mediated by downregulation of potassium channels Kv1.1. It is sensitive to rapamycin and thus may involve activation of the mammalian target of rapamycin complex 1 (mTORC1). LTP IE facilitates PV INs recruitment in CA1 and maintains an excitatory-inhibitory balance. Impaired CA1 PV INs activity or LTP affects network oscillations and memory. However, whether LTP IE in PV INs plays a role in hippocampus-dependent memory remains unknown. Here, we used conditional deletion of the obligatory component of mTORC1, the Regulatory-Associated Protein of mTOR (Raptor), to directly manipulate mTORC1 in PV INs. We found that homozygous, but not heterozygous, conditional knock-out of Rptor resulted in a decrease in CA1 PV INs of mTORC1 signaling via its downstream effector S6 phosphorylation assessed by immunofluorescence. In whole-cell recordings from hippocampal slices, repetitive firing of CA1 PV INs was impaired in mice with either homozygous or heterozygous conditional knock-out of Rptor. High frequency stimulation of Schaffer collateral inputs that induce LTP IE in PV INs of control mice failed to do so in mice with either heterozygous or homozygous conditional knock-out of Rptor in PV INs. At the behavioral level, mice with homozygous or heterozygous conditional knock-out of Rptor showed similar long-term contextual fear memory or contextual fear memory discrimination relative to control mice. Thus, mTORC1 activity in CA1 PV INs regulates repetitive firing and LTP IE but not consolidation of long-term contextual fear memory and context discrimination. Our results indicate that mTORC1 plays cell-specific roles in synaptic plasticity of hippocampal inhibitory interneurons that are differentially involved in hippocampus-dependent learning and memory.
(© 2022. The Author(s).)

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MOP-125985 Canada CIHR; PJT-153311 Canada CIHR

Keywords: CA1 hippocampus; Contextual fear conditioning; GABA interneurons; Raptor conditional knock-out mice; Whole-cell recordings

0 (Parvalbumins)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)

Date Created: 20220617 Date Completed: 20220621 Latest Revision: 20220716

20231215

PMC9204956

10.1186/s13041-022-00941-8

35715811