Changes in the induction and expression of synaptic plasticity
Because glutamatergic LTD has been scarcely explored in the PP – DG
synapses, a relevant finding of this study was the establishment of a
protocol to induce reliable LTD. The exploratory experiments designed to
this end showed that electrical stimulation of MPP, but not LPP, induces
a stable LTD in response to 900 pulses delivered at 3Hz, a stimulation
frequency that mimics the delta–theta range of volley activity of
stellar cells and pyramidal neurons of EC layer II synapsing DG granule
cells (Gloveli et al., 1997; Deshmukh et al., 2010). In a previous
study, Peñasco et al. demonstrated that MPP LTD can be induced with 6000
pulses at 10 Hz, but this required simultaneous blockade of
GABAA receptors and involved activation of the
CB1R (Peñasco et al., 2019). In the present study, LTD
was induced with less electrical stimulation, and GABAergic transmission
remained active; the resulting LTD was stable for up to 90 minutes
without visible signs of a return to the baseline fEPSP value. The LTD
was accompanied by increased PPR, indicating a presynaptic locus for its
expression. As in Peñasco et al., the MPP LTD reported in our study
requires postsynaptic production of 2-AG.
In slices from MK-801-treated animals, LFS induced synaptic potentiation
instead of LTD. The absence of LTD may result from presynaptic
dysregulation in CB1R activity, accelerated breakdown of
2-AG, or altered synthesis of 2-AG at the postsynaptic level. The latter
is unlikely, since physostigmine induced a synaptic depression like that
observed with activation of CB1R in the MK-801
condition. These findings indicate that MK-801-treated animals maintain
functional postsynaptic production of 2-AG, suggesting a potential
dysregulation locus at the presynaptic MPP terminals. In this regard, a
critical finding of this study was that the blockade of the MAGL enzyme
reverted LTD loss in MK-801-treated animals. MAGL is a presynaptically
expressed enzyme that metabolizes 2-AG and is essential in multiple
physiological processes, including neuroplasticity, cognitive
performance, and behavior (Wang et al., 2018a; Zanfirescu et al., 2021).
Our results suggest that transient hypofunction of NMDARs interferes
with the expression of the MAGL enzyme, affecting the MPP’s ability to
express long-term depression of glutamatergic transmission.
We also documented that transient hypofunction of NMDARs hinders the
induction and expression of TBS-induced LTP in the LPP synapse and
attenuates the magnitude but not the expression of LTP in the MPP
synapse. While MPP LTP may be induced in MK-801-treated slices through a
series of redundant signaling pathways, including CaMKII and PKA-ERK1/2
(Wu et al., 2006; Welsby et al., 2009), that assure its postsynaptic
expression, in the LPP – DG synapse, LTP requires postsynaptic
synthesis of 2-AG (Wang et al., 2016), presynaptic activation of
CB1R, and increased neurotransmitter release mediated by
the non-canonic CB1R /FAK/ROCK pathway (Wang et al.,
2018b). Although we did not investigate the mechanisms underlying the
blunted induction of LPP LTP, decreased functional expression of
CB1R receptors or accelerated degradation of 2-AG may
explain the absence of LTP observed in this study.