RESUMO
Wnt proteins activate different signaling pathways, such as the canonical Wnt/ß-catenin signaling pathway and non-canonical ß-catenin-independent signaling pathway and have been related to several functions in central nervous system, including learning and memory. However, whether these signaling pathways are required in the medial prefrontal cortex (mPFC) for fear memory acquisition, consolidation and retrieval remains unclear. To address this question, we submitted male rats to a contextual fear conditioning (CFC) paradigm, and administered canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways inhibitors, DKK1 and SFRP1, respectively, into the prelimbic (PrL) subdivision of the mPFC at different moments and evaluated short-term and long-term memory acquisition, consolidation and retrieval. We found that blocking canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways 15 min before or immediately after CFC training had no effect on STM and LTM of CFC, while their blockade 15 min before the retention test prevented the retrieval of STM and LTM of CFC. These results highlight the importance of the mPFC in fear memory retrieval demonstrating that both canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways participate in this process. To understand how brain systems act on fear memories could provide a new target for the treatment of fear related disorders such as post-traumatic stress disorder and other anxiety disorders.
Assuntos
Medo , beta Catenina , Animais , Cálcio/metabolismo , Medo/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Memória/fisiologia , Córtex Pré-Frontal/metabolismo , Ratos , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
Ever since their discoveries, the Wnt pathways have been consistently associated with key features of cellular development, including metabolism, structure and cell fate. The three known pathways (the canonical Wnt/ß-catenin and the two non-canonical Wnt/Ca++ and Wnt/JNK/PCP pathways) participate in complex networks of interaction with a wide range of regulators of cell function, such as GSK-3ß, AKT, PKC and mTOR, among others. These proteins are known to be involved in the formation and maintenance of memory. Currently, studies with Wnt and memory have shown that the canonical and non-canonical pathways play key roles in different processes associated with memory. So, in this review we briefly summarize the different roles that Wnt signaling can play in neurons and in memory, as well as in Alzheimer's disease, focusing towards animal studies. We start with the molecular characterization of the family and its receptors, as well as the most commonly used drugs for pharmacological manipulations. Next, we describe its role in synaptic plasticity and memory, and how the regulations of these pathways affect crucial features of neuronal function. Furthermore, we succinctly present the current knowledge on how the Wnt pathways are implicated in Alzheimer's disease, and how studies are seeing them as a potential candidate for effective treatments. Lastly, we point toward challenges of Wnt research, and how knowledge on these pathways can lead towards a better understanding of neurobiological and pathological processes.
Assuntos
Memória/fisiologia , Plasticidade Neuronal , Via de Sinalização Wnt/fisiologia , Doença de Alzheimer/metabolismo , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neurônios/metabolismoRESUMO
Fear memories allow animals to recognize and adequately respond to dangerous situations. The prelimbic cortex (PrL) is a crucial node in the circuitry that encodes contextual fear memory, and its activity is central for fear memory expression over time. However, while PrL has been implicated in contextual fear memory storage, the molecular mechanisms underlying its maintenance remain unclear. Protein kinase M zeta (PKMζ) is a persistently active enzyme which has been shown to maintain many forms of memories by inhibiting the endocytosis of GluA2-containing AMPA receptors. Therefore, we hypothesized that PKMζ action upon GluA2-containing AMPARs could be a mechanism for contextual fear memory maintenance in the PrL. To test this hypothesis, we trained rats in a contextual fear conditioning (CFC) paradigm and administered intra-PrL infusions of the PKMζ inhibitor ZIP, the GluA2-dependent endocytosis inhibitor GluA23Y or the inactive peptide GluA23Y(s), either two or twenty days after conditioning, and assessed long-term memory retention twenty-four hours later. We found that acute inhibition of GluA2-dependent AMPAR endocytosis in the PrL does not affect recent or remote contextual fear memory maintenance. Also, PKMζ inhibition in the PrL does not impair the maintenance of recent contextual fear memory. However, we found that inhibition of prelimbic PKMζ at a remote time point disrupts contextual fear memory maintenance, and that blocking GluA2-dependent removal of AMPARs prevents this impairment. Our results confirm the central role of PrL in fear memory and identify PKMζ-induced inhibition of GluA2-containing AMPAR endocytosis as a key mechanism governing remote contextual fear memory maintenance.
Assuntos
Medo , Memória de Longo Prazo , Memória , Proteína Quinase C , Receptores de AMPA , Animais , Endocitose/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Memória de Longo Prazo/fisiologia , Proteína Quinase C/fisiologia , Ratos , Receptores de AMPA/fisiologiaRESUMO
Acquired information is stabilized into long-term memory through a process known as consolidation. Though, after consolidation, when stored information is retrieved they can be again susceptible, allowing modification, updating and strengthening and to be re-stabilized they need a new process referred to as memory reconsolidation. However, the molecular mechanisms of recognition memory consolidation and reconsolidation are not fully understood. Also, considering that the study of the link between synaptic proteins is key to understanding of memory processes, we investigated, in male Wistar rats, molecular mechanisms in the hippocampus involved on object recognition memory (ORM) consolidation and reconsolidation. We verified that the blockade of AMPA receptors (AMPAr) and L-VDCCs calcium channels impaired ORM consolidation and reconsolidation when administered into CA1 immediately after sample phase or reactivation phase and that these impairments were blocked by the administration of AMPAr agonist and of neurotrophin BDNF. Also, the blockade of CaMKII impaired ORM consolidation when administered 3â¯h after sample phase but had no effect on ORM reconsolidation and its effect was blocked by the administration of BDNF, but not of AMPAr agonist. So, this study provides new evidence of the molecular mechanisms involved on the consolidation and reconsolidation of ORM, demonstrating that AMPAr and L-VDCCs are necessary for the consolidation and reconsolidation of ORM while CaMKII is necessary only for the consolidation and also that there is a link between BDNF and AMPAr, L-VDCCs and CaMKII as well as a link between AMPAr and L-VDCCs on ORM consolidation and reconsolidation.