The transient hypofunction of NMDARs during early postnatal
development impairs the CB1R-dependent LTD at the MPP –
DG synapse.
If CB1R activation is a necessary step for the induction
of MPP LTD, and previous studies have documented altered
CB1R functionality in several schizophrenia models
(Kaminitz et al., 2014; Szűcs et al., 2016; Osborne et al., 2019), it is
plausible that MK-801-treated slices could exhibit altered LTD
induction. We tested this prediction by applying LFS (900 pulses at 3
Hz) to the MK-801-treated slices. As shown in Figure 3d, LFS failed to
induce LTD at the MPP – DG synapse. Moreover, the stimulation protocol
induced potentiation of the MPP fEPSP (fEPSP at 90 min post-LFS in
MK-801-treated slices: 139.7 ±
23.12% of baseline, n = 6 slices / 6 animals, Kruskal-Wallis
test, Dunn’s post-hoc test, P < 0.05 vs. control;
traces and red bars in Figure 3c-d). The synaptic response was sensitive
to perfusion of DCG-IV, confirming its presynaptic MPP nature (fEPSP in
the presence of DCG-IV: 42.13 ± 8.5% of baseline,
Kruskal-Wallis test, Dunn’s
post-hoc test, P < 0.05 vs. control; red bars in Figure
3e). Interestingly, the anomalous synaptic potentiation observed in the
MK-801-treated slices did not alter the MPP PPF
(PPR in control condition: 1.43 ±
0.07; at 90 min post-LFS: 1.5 ± 0.09; Wilcoxon test, P> 0.05; red bars in Figure 3f), suggesting altered
functionality of postsynaptic glutamate receptors. The cumulative
probability chart in Figure 3g summarizes the magnitude of the MPP LTD
observed in control slices (black line), the blockade of LTD in the
presence of AM 251 (gray line), and the synaptic response of
MK-801-treated slices (red line). These results demonstrate that
transient hypofunction of NMDARs during early postnatal development
impairs the presynaptic-mediated, CB1R-dependent LTD and
triggers aberrant forms of synaptic plasticity in the MPP – DG synapse.