RESUMEN
CaMK2N1 and CaMK2N2 (also known as CaMKIINα and ß) are endogenous inhibitors of calcium/calmodulin-dependent kinase II (CaMKII), an enzyme critical for memory and long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning. CaMK2N1/2 mRNAs are rapidly and differentially upregulated in the hippocampus and amygdala after acquisition or retrieval of fear memory. Moreover, CaMK2N2 protein levels increase after contextual fear conditioning. Therefore, it was proposed that CaMK2N1/2 genes (Camk2n1/2) could be immediate-early genes transcribed promptly (30-60 min) after training. As a first approach to explore a role in synaptic plasticity, we assessed a possible regulation of Camk2n1/2 during the expression phase of LTP in hippocampal CA3-CA1 connections in rat brain slices. Quantitative PCR revealed that Camk2n1, but not Camk2n2, is upregulated 60 min after LTP induction by Schaffer collaterals high-frequency stimulation. We observed a graded, significant positive correlation between the magnitude of LTP and Camk2n1 change in individual slices, suggesting a coordinated regulation of these properties. If mRNA increment actually resulted in the protein upregulation in plasticity-relevant subcellular locations, CaMK2N1 may be involved in CaMKII fine-tuning during LTP maintenance or in the regulation of subsequent plasticity events (metaplasticity).
Asunto(s)
Proteínas de Unión al Calcio/genética , Hipocampo/metabolismo , Potenciación a Largo Plazo , Animales , Proteínas de Unión al Calcio/metabolismo , Hipocampo/fisiología , Masculino , Plasticidad Neuronal , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Regulación hacia ArribaRESUMEN
Accruing evidence supports the hypothesis that memory deficits in early Alzheimer Disease (AD) might be due to synaptic failure caused by accumulation of intracellular amyloid beta (Aß) oligomers, then secreted to the extracellular media. Transgenic mouse AD models provide valuable information on AD pathology. However, the failure to translate these findings to humans calls for models that better recapitulate the human pathology. McGill-R-Thy1-APP transgenic (Tg) rat expresses the human amyloid precursor protein (APP751) with the Swedish and Indiana mutations (of familial AD), leading to an AD-like slow-progressing brain amyloid pathology. Therefore, it offers a unique opportunity to investigate learning and memory abilities at early stages of AD, when Aß accumulation is restricted to the intracellular compartment, prior to plaque deposition. Our goal was to further investigate early deficits in memory, particularly long-term memory in McGill-R-Thy1-APP heterozygous (Tg+/-) rats. Short-term- and long-term habituation to an open field were preserved in 3-, 4-, and 6-month-old (Tg+/-). However, long-term memory of inhibitory avoidance to a foot-shock, novel object-recognition and social approaching behavior were seriously impaired in 4-month-old (Tg+/-) male rats, suggesting that they are unable to either consolidate and/or evoke such associative and discriminative memories with aversive, emotional and spatial components. The long-term memory deficits were accompanied by increased transcript levels of genes relevant to synaptic plasticity, learning and memory processing in the hippocampus, such as Grin2b, Dlg4, Camk2b, and Syn1. Our findings indicate that in addition to the previously well-documented deficits in learning and memory, McGill-R-Thy1-APP rats display particular long-term-memory deficits and deep social behavior alterations at pre-plaque early stages of the pathology. This highlights the importance of Aß oligomers and emphasizes the validity of the model to study AD-like early processes, with potentially predictive value.