RESUMEN
Long-lasting changes in dendritic spines provide a physical correlate for memory formation and persistence. LIM kinase (LIMK) plays a critical role in orchestrating dendritic actin dynamics during memory processing, since it is the convergent downstream target of both the Rac1/PAK and RhoA/ROCK pathways that in turn induce cofilin phosphorylation and prevent depolymerization of actin filaments. Here, using a potent LIMK inhibitor (BMS-5), we investigated the role of LIMK activity in the dorsal hippocampus during contextual fear memory in rats. We first found that post-training administration of BMS-5 impaired memory consolidation in a dose-dependent manner. Inhibiting LIMK before training also disrupted memory acquisition. We then demonstrated that hippocampal LIMK activity seems to be critical for memory retrieval and reconsolidation, since both processes were impaired by BMS-5 treatment. Contextual fear memory extinction, however, was not sensitive to the same treatment. In conclusion, our findings demonstrate that hippocampal LIMK activity plays an important role in memory acquisition, consolidation, retrieval, and reconsolidation during contextual fear conditioning.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Extinción Psicológica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Quinasas Lim/antagonistas & inhibidores , Consolidación de la Memoria/efectos de los fármacos , Memoria/efectos de los fármacos , Animales , Condicionamiento Psicológico/efectos de los fármacos , Miedo/efectos de los fármacos , Masculino , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Over the past years, extensive research in experimental cognitive neuroscience has provided a comprehensive understanding about the role of ionotropic glutamate receptor (IGluR)-dependent signaling underpinning postsynaptic plasticity induced by long-term potentiation (LTP), the leading cellular basis of long-term memory (LTM). However, despite the fact that iGluR-mediated postsynaptic plasticity regulates the formation and persistence of LTP and LTM, here we discuss the state-of-the-art regarding the mechanisms underpinning both LTP and LTM decay. First, we review the crucial roles that iGluRs play on memory encoding and stabilization. Second, we discuss the latest findings in forgetting considering hippocampal GluA2-AMPAR trafficking at postsynaptic sites as well as dendritic spine remodeling possibly involved in LTP decay. Third, on the role of retrieving consolidated LTMs, we discuss the mechanisms involved in memory destabilization that occurs followed reactivation that share striking similarities with the neurobiological basis of forgetting. Fourth, since different AMPAR subunits as well as postsynaptic scaffolding proteins undergo ubiquitination, the ubiquitin-proteasome system (UPS) is discussed in light of memory decay. In conclusion, we provide an integrated overview revealing some of the mechanisms determining memory forgetting that are mediated by iGluRs. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
Asunto(s)
Hipocampo/fisiología , Potenciación a Largo Plazo , Memoria a Largo Plazo/fisiología , Receptores AMPA/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/fisiología , Animales , Espinas Dendríticas/fisiología , Hipocampo/metabolismo , Humanos , Recuerdo Mental/fisiología , Complejo de la Endopetidasa Proteasomal/fisiología , Transporte de Proteínas , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , UbiquitinaciónRESUMEN
In the past decades, the cellular and molecular mechanisms underlying memory consolidation, reconsolidation, and extinction have been well characterized. However, the neurobiological underpinnings of forgetting processes remain to be elucidated. Here we used behavioral, pharmacological and electrophysiological approaches to explore mechanisms controlling forgetting. We found that post-acquisition chronic inhibition of the N-methyl-D-aspartate receptor (NMDAR), L-type voltage-dependent Ca(2+) channel (LVDCC), and protein phosphatase calcineurin (CaN), maintains long-term object location memory that otherwise would have been forgotten. We further show that NMDAR activation is necessary to induce forgetting of object recognition memory. Studying the role of NMDAR activation in the decay of the early phase of long-term potentiation (E-LTP) in the hippocampus, we found that ifenprodil infused 30 min after LTP induction in vivo blocks the decay of CA1-evoked postsynaptic plasticity, suggesting that GluN2B-containing NMDARs activation are critical to promote LTP decay. Taken together, these findings indicate that a well-regulated forgetting process, initiated by Ca(2+) influx through LVDCCs and GluN2B-NMDARs followed by CaN activation, controls the maintenance of hippocampal LTP and long-term memories over time.
Asunto(s)
Calcineurina/metabolismo , Canales de Calcio Tipo L/metabolismo , Memoria a Largo Plazo/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Conducta Animal , Hipocampo/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Memoria a Largo Plazo/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/farmacología , Ratas , Ratas Wistar , Potenciales Sinápticos/efectos de los fármacosRESUMEN
Despite the fact that the cannabinoid receptor type 1 (CB1R) plays a pivotal role in emotional memory processing in different regions of the brain, its function in the retrosplenial cortex (RSC) remains unknown. Here, using contextual fear conditioning in rats, we showed that a post-training intra-RSC infusion of the CB1R antagonist AM251 impaired, and the agonist CP55940 improved, long-term memory consolidation. Additionally, a post-reactivation infusion of AM251 enhanced memory reconsolidation, while CP55940 had the opposite effect. Finally, AM251 blocked extinction, whereas CP55940 facilitated it and maintained memory extinguished over time. Altogether, our data strongly suggest that the cannabinoid system of the RSC modulates emotional memory.