Introduction
A growing body of evidence indicates that hypofunction of
N-methyl-D-aspartate receptors (NMDARs) represents a convergence point
for the onset and further development of psychiatric disorders,
including autism and schizophrenia (Snyder and Gao, 2013; Forsyth and
Lewis, 2017; Nakazawa and Sapkota, 2020). The genetic/chemogenetic
ablation or pharmacological blockade of NMDARs during critical periods
of brain development has successfully reproduced the negative,
cognitive, and psychotic symptoms associated with schizophrenia
(Jeevakumar et al., 2015; Kjaerby et al., 2017; Seshadri et al., 2018;
Nakao et al., 2019; Segev et al., 2020). Therefore, hypofunction of
NMDARs by neonatal blockade with antagonists such as MK-801 leads to
alterations in the release process of dopamine, glutamate, and GABA
(Nakao et al., 2019; Segev et al., 2020; Márquez et al., 2023);
alterations in the functional expression of ion channels and
postsynaptic receptors in the hippocampus (Griego et al., 2022; Márquez
et al., 2023); and behavioral deficits that resemble the negative and
cognitive symptoms of schizophrenia (Kjaerby et al., 2017; Seshadri et
al., 2018; Segev et al., 2020).
It is now accepted that the hippocampus, a brain region essential for
cognitive processing, the formation of new memories (Eichenbaum, 2004;
Nadel et al., 2012), and the development of social behaviors
(Lopez-Rojas et al., 2022), is central in the pathophysiology of
schizophrenia (Tamminga et al., 2010; Segev et al., 2020). In line with
this tenet, the dentate gyrus (DG), the somatosensorial gate of the
hippocampus, shows the greatest volumetric loss, neuroanatomic
disorganization, and altered glutamatergic/GABAergic transmission in
schizophrenic individuals and animal models (Li et al., 2015; Stan et
al., 2015; Nakahara et al., 2019; Griego et al., 2022). The DG receives
and processes somatosensorial and spatial information from the
entorhinal cortex via the lateral perforant pathway (LPP) and the medial
perforant pathway (MPP), respectively (Hunsaker et al., 2007;
Fernández-Ruiz et al., 2021), and minimizes the overlapping of new
memories with highly similar content via a theoretical mechanism known
as pattern separation (Yassa and Stark, 2011).
Additionally, multiple works have shown the relevance of the cannabinoid
1 receptor (CB1R) for the induction of long-term
depression and potentiation in the PP – DG synapses (Wu et al., 2006;
Wang et al., 2016, 2018b; Peñasco et al., 2019; Fontaine et al., 2020).
Interestingly, dysregulation of NMDARs and CB1R is
present in animal models and schizophrenic individuals (Szűcs et al.,
2016; Forsyth and Lewis, 2017; Osborne et al., 2019; Márquez et al.,
2023). Despite the potential repercussions of the altered functionality
of NMDARs and CB1R within the LPP and MPP – DG
synapses, little is known about the possibly altered functionality of
the DG in schizophrenia.
This study identified neurophysiological alterations endured by LPP and
MPP – DG synapses in response to the transient hypofunction of NMDARs
during early postnatal development. The changes in the neurotransmitter
release process, altered synaptic strength, and dysregulated synaptic
filtering found in these synapses are accompanied by changes in the
induction and expression of LTP and LTD and dysfunction of the
presynaptic activity of the CB1R. We also demonstrated
that induction of LTD is restored by fostering the
2-Arachidonoylglycerol (2-AG) signaling, the endogenous ligand of the
CB1R, via negative modulation of monoacylglycerol lipase (MAGL).
Finally, we show for the first time that spatial discrimination, a
cognitive task in which the DG takes part, deteriorates in response to
neonatal hypofunction of NMDARs.Methods