PMID- 37857485 OWN - NLM STAT- MEDLINE DCOM- 20231216 LR - 20240119 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 43 IP - 50 DP - 2023 Dec 13 TI - Stabilizing Immature Dendritic Spines in the Auditory Cortex: A Key Mechanism for mTORC1-Mediated Enhancement of Long-Term Fear Memories. PG - 8744-8755 LID - 10.1523/JNEUROSCI.0204-23.2023 [doi] AB - Mammalian target of rapamycin (mTOR) pathway has emerged as a key molecular mechanism underlying memory processes. Although mTOR inhibition is known to block memory processes, it remains elusive whether and how an enhancement of mTOR signaling may improve memory processes. Here we found in male mice that the administration of VO-OHpic, an inhibitor of the phosphatase and tensin homolog (PTEN) that negatively modulates AKT-mTOR pathway, enhanced auditory fear memory for days and weeks, while it left short-term memory unchanged. Memory enhancement was associated with a long-lasting increase in immature-type dendritic spines of pyramidal neurons into the auditory cortex. The persistence of spine remodeling over time arose by the interplay between PTEN inhibition and memory processes, as VO-OHpic induced only a transient immature spine growth in the somatosensory cortex, a region not involved in long-term auditory memory. Both the potentiation of fear memories and increase in immature spines were hampered by rapamycin, a selective inhibitor of mTORC1. These data revealed that memory can be potentiated over time by the administration of a selective PTEN inhibitor. In addition to disclosing new information on the cellular mechanisms underlying long-term memory maintenance, our study provides new insights on the molecular processes that aid enhancing memories over time.SIGNIFICANCE STATEMENT The neuronal mechanisms that may help improve the maintenance of long-term memories are still elusive. The inhibition of mammalian-target of rapamycin (mTOR) signaling shows that this pathway plays a crucial role in synaptic plasticity and memory formation. However, whether its activation may strengthen long-term memory storage is unclear. We assessed the consequences of positive modulation of AKT-mTOR pathway obtained by VO-OHpic administration, a phosphatase and tensin homolog inhibitor, on memory retention and underlying synaptic modifications. We found that mTOR activation greatly enhanced memory maintenance for weeks by producing a long-lasting increase of immature-type dendritic spines in pyramidal neurons of the auditory cortex. These results offer new insights on the cellular and molecular mechanisms that can aid enhancing memories over time. CI - Copyright (c) 2023 the authors. FAU - Concina, Giulia AU - Concina G AUID- ORCID: 0000-0002-0895-5384 AD - Department of Neuroscience, University of Turin, Turin, 10125, Italy. FAU - Gurgone, Antonia AU - Gurgone A AD - Department of Neuroscience, University of Turin, Turin, 10125, Italy. FAU - Boggio, Elena M AU - Boggio EM AD - Institute of Neuroscience, National Research Council, Pisa, 56124, Italy. FAU - Raspanti, Alessandra AU - Raspanti A AD - Department of Neuroscience, University of Turin, Turin, 10125, Italy. FAU - Pizzo, Riccardo AU - Pizzo R AD - Department of Neuroscience, University of Turin, Turin, 10125, Italy. FAU - Morello, Noemi AU - Morello N AD - Department of Neuroscience, University of Turin, Turin, 10125, Italy. FAU - Castroflorio, Enrico AU - Castroflorio E AD - Department of Neuroscience, University of Turin, Turin, 10125, Italy. FAU - Pizzorusso, Tommaso AU - Pizzorusso T AD - Institute of Neuroscience, National Research Council, Pisa, 56124, Italy. AD - Scuola Normale Superiore, Biology Laboratory BIO@SNS, Pisa, 56124, Italy. FAU - Sacchetti, Benedetto AU - Sacchetti B AUID- ORCID: 0000-0002-8695-8310 AD - Department of Neuroscience, University of Turin, Turin, 10125, Italy benedetto.sacchetti@unito.it maurizio.giustetto@unito.it. FAU - Giustetto, Maurizio AU - Giustetto M AUID- ORCID: 0000-0003-1323-4060 AD - Department of Neuroscience, University of Turin, Turin, 10125, Italy benedetto.sacchetti@unito.it maurizio.giustetto@unito.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231213 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (VO-OHpic) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - 0 (Tensins) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) RN - EC 3.1.3.2 (Phosphoric Monoester Hydrolases) SB - IM MH - Male MH - Mice MH - Animals MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - *Proto-Oncogene Proteins c-akt/metabolism MH - *Auditory Cortex/metabolism MH - Dendritic Spines/metabolism MH - Tensins/metabolism MH - Memory, Long-Term/physiology MH - TOR Serine-Threonine Kinases/metabolism MH - Memory, Short-Term/physiology MH - Sirolimus/pharmacology MH - Fear/physiology MH - Phosphoric Monoester Hydrolases/metabolism MH - Mammals PMC - PMC10727119 OTO - NOTNLM OT - PTEN OT - auditory cortex OT - dendritic spines OT - inhibition OT - learning and memory OT - mTOR EDAT- 2023/10/20 00:43 MHDA- 2023/12/17 09:43 PMCR- 2024/06/13 CRDT- 2023/10/19 21:42 PHST- 2023/02/02 00:00 [received] PHST- 2023/08/30 00:00 [revised] PHST- 2023/09/04 00:00 [accepted] PHST- 2024/06/13 00:00 [pmc-release] PHST- 2023/12/17 09:43 [medline] PHST- 2023/10/20 00:43 [pubmed] PHST- 2023/10/19 21:42 [entrez] AID - JNEUROSCI.0204-23.2023 [pii] AID - JN-RM-0204-23 [pii] AID - 10.1523/JNEUROSCI.0204-23.2023 [doi] PST - epublish SO - J Neurosci. 2023 Dec 13;43(50):8744-8755. doi: 10.1523/JNEUROSCI.0204-23.2023.