4.1 Effects of brief EE exposure in the medial prefrontal
cortex
In the mPFC, brief EE exposure selectively increased GluN2A levels,
leading to a significant increase in GluN2A/GluN2B ratio. The analysis
of the AMPA receptor, instead, revealed a decrease of GluA1 and an
increase of GluA2 subunits expression leading to a decrease of
GluA1/GluA2 ratio. This suggests that brief EE exposure alters the
composition of these receptors which might contribute to changes in the
homeostasis of the glutamate system.
According to the literature, GluN2A/GluN2B ratio change correlates with
modifications of the threshold for LTP and LTD (Chiamulera et
al. , 2020). For instance, while lack of sensory experiences, such as
light deprivation, decreases the GluN2A/GluN2B ratio, restoring visual
experience rapidly increases the GluN2A/GluN2B ratio, raising the
LTP/LTD threshold in the visual cortex (Quinlan et al. , 1999;
Philpot et al. , 2003). This bidirectional change of
LTP/LTD threshold induced by rapid modification of NMDAR subunits
composition has been proposed as a demonstration of metaplasticity
(Kirkwood et al. , 1996; Philpot et al. , 2003). Similarly,
we hypothesize that brief EE may cause an increase in LTP/LTD threshold,
by inducing a rapid switch of NMDARs with a higher proportion of GluN2A
subunits, thus reducing Ca2+ influx.
In line with an ‘overstimulation hypothesis’, these AMPA/NMDA receptors
changes are coupled with an increase of the related scaffolding proteins
levels both in the PSD fraction (SAP102, SAP97, GRIP) and in the whole
cortical homogenate (SAP102, SAP97, GRIP, PSD95). Particularly, it is
interesting to note that while GluA1 expression is reduced in the PSD,
the expression of the specific scaffolding protein of this receptor,
SAP97, is significantly elevated, presumably as an adaptive mechanism to
anchor more tightly this receptor at the membrane. Considering their
role in the formation, trafficking, and stabilization of NMDARs and
AMPARs at excitatory synapses (Kim et al. , 2005; Vickers et
al. , 2006), these EE-induced scaffolding proteins changes could be
involved in increased membrane stability of new glutamate receptors
configuration induced by EE exposure. Consistently with this hypothesis,
Arc/Arg3.1 increased in the PSD after EE exposure, an observation in
line with its involvement in a simultaneous strengthening of stimulated
synapses and maintaining weakness at non-potentiated synapses through
AMPARs trafficking modulation (Zhang & Bramham, 2021). Finally, the
overstimulation hypothesis is further accounted for by the up-regulation
of vGluT1, which promotes glutamate release (Li et al. , 2020),
and that may be partly countered by the increased levels of GLT-1, which
is chiefly responsible for glutamate reuptake (Shigeri et al. ,
2004).
Taken together, these neuroplastic changes occurring at glutamatergic
synapses, induced by brief EE exposure, could reflect a limitation of
mPFC synaptic excitability (and in turn a reduction of its inhibitory
action on subcortical regions) by further stimuli (i.e.,
reward-associated stimuli) as a consequence to previous strong cortical
activation. In line with a reduction of cortical inhibitory activity, we
previously reported that brief EE exposure enhanced rather than
inhibited context-induced sucrose-seeking (Pintori et al. ,
2022a). Electrophysiological experiments would be needed to better
understand the change of synaptic properties in the mPFC under EE
conditions.