Abstract
N-methyl-D-aspartate receptors are heterotetramers composed of two GluN1 obligatory subunits and two regulatory subunits. In cognitive-related brain structures, GluN2A and GluN2B are the most abundant regulatory subunits, and their expression is subjected to tight regulation. During development, GluN2B expression is characteristic of immature synapses, whereas GluN2A is present in mature ones. This change in expression induces a shift in GluN2A/GluN2B ratio known as developmental switch. Moreover, modifications in this relationship have been associated with learning and memory, as well as different pathologies. In this work, we used a specific shRNA to induce a reduction in GluN2A expression after the developmental switch, both in vitro in primary cultured hippocampal neurons and in vivo in adult male Wistar rats. After in vitro characterization, we performed a cognitive profile and evaluated seizure susceptibility in vivo. Our in vitro results showed that the decrease in the expression of GluN2A changes GluN2A/GluN2B ratio without altering the expression of other regulatory subunits. Moreover, rats expressing the anti-GluN2A shRNA in vivo displayed an impaired contextual fear-conditioning memory. In addition, these animals showed increased seizure susceptibility, in terms of both time and intensity, which led us to conclude that deregulation in GluN2A expression at the hippocampus is associated with seizure susceptibility and learning–memory mechanisms.
Highlights
N-methyl-D-aspartate receptors (NMDAR) are one of the most important ionotropic receptors responsible for glutamatergic excitatory transmission in the brain, mainly because they are considered the postsynaptic molecular coincidence detector of presynaptic and postsynaptic activity (Wigström and Gustafsson, 1986; Kandel et al, 2012)
It is well established that GluN2A and GluN2B are the main NMDAR regulatory subunits expressed in the hippocampus and cortical areas (Lau and Zukin, 2007; Yashiro and Philpot, 2008; Paoletti et al, 2013; Sanz-Clemente et al, 2013; Shipton et al, 2014), and their expression is tightly regulated in a temporal pattern during development and synapse maturation
In these models, decreased GluN2A expression could be compensated by mechanisms that contribute to the normal development of neurons
Summary
N-methyl-D-aspartate receptors (NMDAR) are one of the most important ionotropic receptors responsible for glutamatergic excitatory transmission in the brain, mainly because they are considered the postsynaptic molecular coincidence detector of presynaptic and postsynaptic activity (Wigström and Gustafsson, 1986; Kandel et al, 2012). Sepulveda et al (2010) and Gambrill and Barria (2011) described that neurons where GluN2A was expressed at lower levels showed increased dendritic spine density compared to controls (Sepulveda et al, 2010; Gambrill and Barria, 2011) In both cases, GluN2A silencing was induced before the developmental switch, blocking the rise in GluN2A expression and the consequent developmental maturation processes. In the cases where GluN2A was knocked out (KO), no changes in several long-term memory tasks were observed (Bannerman et al, 2008, 2012; Bannerman, 2009) Taking into account these antecedents, we hypothesized that the reduction in GluN2A expression after the developmental switch could modify the GluN2A/GluN2B ratio and lead to a change in behavior and seizure susceptibility. These animals showed an increase in seizure susceptibility, both in time and intensity, suggesting that the decrease in GluN2A expression in a mature system would be associated with seizure onset and contextual learning– memory acquisition
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