4.3 Effects of brief EE exposure in the hippocampus
The analysis of the Hipp revealed a different situation in comparison to mPFC and NAc. Brief EE exposure only slightly altered glutamatergic postsynaptic signaling in this brain area. The most relevant effect is the reduced GluN2A/GluN2B ratio in the PSD, due to a decrease of GluN2A and an increase of GluN2B receptor subunits expression together with a reduction in SAP102 expression. This change of synaptic NMDA receptors configuration may reflect a decrease of the LTP/LTD threshold, in line with the reduced presynaptic glutamate release as evidenced by a significant down-regulation of vGluT1. Our evidence is consistent with the literature showing that EE exposure (both long- and short-term) facilitates the LTP in CA1 (see review (Ohline & Abraham, 2019)). It is plausible that this EE-induced NMDARs hippocampal change may contribute to an enhancement of learning and memory abilities, such as spatial recognition. Moreover, GluN2B-containing receptors in the dorsal Hipp are necessary for drug context-induced cocaine-seeking behavior (Xieet al. , 2013), as well as memory reconsolidation (Wells et al. , 2016), and relapse even after a long period of abstinence from cocaine self-administration (Werner et al. , 2020). In line with this speculation, we previously reported that brief EE exposure improves discrimination efficiency (an index of instrumental learning and memory) and increases sucrose-seeking behavior during both contextual-memory reactivation session and renewal test (Pintori et al. , 2022a), suggesting that the increased hippocampal GluN2B-containing receptor expression might be the underlying mechanism of such behaviors.
Differently from mPFC and NAc, EE did not change postsynaptic AMPA receptor expression and subunit configuration in the Hipp, while reducing the expression of AMPA receptor scaffolding proteins SAP97 and GRIP in the PSD, suggesting reduced AMPA receptor retention at the synaptic site. Together with a more mobile pool of GluN2B-containing NMDA receptors (Groc et al. , 2006) and supported by increased Arc/Arg3.1 levels (Chowdhury et al. , 2006), this effect might contribute to altering the synaptic strength of the excitatory synapse thus leading to a less stable hippocampal synapse.
These changes, together with the decreased GluN2A/GluN2B ratio, may represent a ‘canonical’ metaplastic mechanism to set up glutamatergic synapses to respond more robustly to future stimulations/experiences, and subsequence learning (Chiamulera et al. , 2020).