There has been a significant increase in the consumption of cannabis for both recreational and medicinal purposes in recent years, and its use can have long-term consequences on cognitive functions, including memory. Here, we review the immediate and long-term effects of cannabis and its derivatives on glutamatergic neurotransmission, with a focus on both the presynaptic and postsynaptic alterations. Several factors can influence cannabinoid-mediated changes in glutamatergic neurotransmission, including dosage, sex, age, and frequency of use. Acute exposure to cannabis typically inhibits glutamate release, whereas chronic use tends to increase glutamate release. Conversely, the postsynaptic alterations are more complicated than the presynaptic effects, as cannabis can affect the glutamate receptor expression and the downstream signaling of glutamate. All these effects ultimately influence cognitive functions, particularly memory. This review will cover the current research on glutamate–cannabis interactions, as well as the future directions of research needed to understand cannabis-related health effects and neurological and psychological aspects of cannabis use.

Cannabis is now one of the most commonly used illicit substances among pregnant women. This is particularly concerning since developmental exposure to cannabinoids can elicit enduring neurofunctional and cognitive alterations. This study investigates the mechanisms of learning and memory deficits resulting from prenatal cannabinoid exposure (PCE) in adolescent offspring. The synthetic cannabinoid agonist WIN55,212-2 was administered to pregnant rats, and a series of behavioral, electrophysiological, and immunochemical studies were performed to identify potential mechanisms of memory deficits in the adolescent offspring. Hippocampal-dependent memory deficits in adolescent PCE animals were associated with decreased long-term potentiation (LTP) and enhanced long-term depression (LTD) at hippocampal Schaffer collateral-CA1 synapses, as well as an imbalance between GluN2A- and GluN2B-mediated signaling. Moreover, PCE reduced gene and protein expression of neural cell adhesion molecule (NCAM) and polysialylated-NCAM (PSA-NCAM), which are critical for GluN2A and GluN2B signaling balance. Administration of exogenous PSA abrogated the LTP deficits observed in PCE animals, suggesting PSA mediated alterations in GluN2A- and GluN2B- signaling pathways may be responsible for the impaired hippocampal synaptic plasticity resulting from PCE. These findings enhance our current understanding of how PCE affects memory and how this process can be manipulated for future therapeutic purposes.

This review synthesizes preclinical evidence on the behavioral and neurobiological effects of cannabis exposure during prenatal and adolescent developmental periods, with a focus on anxiety, social behavior, learning and memory, and associated brain changes. Understanding the differential impact of cannabis exposure across these windows is critical, given the increasing prevalence of cannabis use and the rising potency of its primary psychoactive component, delta-9-tetrahydrocannabinol (THC). Both prenatal and adolescent periods represent vulnerable windows for disruption of the endocannabinoid system, which plays a central role in typical neurodevelopment. Exogenous activation of this system via THC can lead to atypical brain maturation and subsequent behavioral impairments. These impairments are associated with region-specific alterations in cortical and subcortical structures and are highly dependent on the timing of exposure. For instance, prenatal exposure may disrupt medial prefrontal cortex development, leading to long-term social deficits while sparing memory function. In contrast, adolescent exposure tends to impair hippocampal function, resulting in learning and memory deficits. The manuscript is organized developmentally, beginning with the effects of prenatal exposure and then discussing consequences of adolescent exposure. By delineating the distinct behavioral and neurobiological outcomes associated with the timing of cannabis exposure, this review highlights the importance of developmental stage in assessing the risks of exogenous cannabinoid use and identifies critical periods for targeted research and intervention.

Aim: The hormone adiponectin impacts various facets of brain function, including neurogenesis, energy homeostasis, and synaptic processes. The use of adiponectin or adiponectin receptor agonists may protect against Alzheimer's disease (AD) and reduce AD pathology. Here, we investigated the ability of the adiponectin receptor agonist, AdipoRon, to restore synaptic function in an AD mouse model and the underlying mechanism. Methods: Acute hippocampal slices from 3xTg‐AD mice and age‐matched controls were used to evaluate the ability of AdipoRon to rescue synaptic deficits in an AD model. Slices were incubated in AdipoRon or other pharmacological agents, followed by electrophysiological field recordings to evaluate synaptic function and plasticity. Signaling pathway alterations were evaluated by Western blot, with a focus on AMP‐activated protein kinase (AMPK) signaling. Results: Incubation of hippocampal slices with AdipoRon ameliorated long‐term potentiation (LTP) and basal synaptic transmission deficits in 3xTg‐AD mice. AdipoRon was unable to restore these parameters in the presence of the AMPK inhibitor, Compound C. AdipoRon altered presynaptic parameters by a mechanism that did not appear to be solely dependent on AMPK. AdipoRon slice incubation was associated with activation of AMPK, inhibition of GSK3β, and altered glutamatergic receptor subunit phosphorylation based on Western blot analysis. Conclusion: Activation of adiponectin receptors restores synaptic function in an AD model in part through AMPK signaling. These results warrant further investigation into adiponectin receptor agonists as a novel approach for AD prevention or treatment.

Background: Prenatal cannabinoid exposure (PCE) causes neurodevelopmental impairments affecting learning and memory; however, the receptor-level interactions underlying these cognitive deficits remain poorly understood. This study investigated whether a moderate dose of prenatal Δ⁹-tetrahydrocannabinol (THC) exposure alters the biophysical properties of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are critical mediators of excitatory neurotransmission and synaptic plasticity. Methods: Pregnant Sprague-Dawley rats received a moderate dose (5 mg/kg) of THC or vehicle control via oral gavage throughout gestation and early postnatal development. Single-channel electrophysiological activity of the AMPA receptors (AMPARs) was recorded using patch-clamp techniques on synaptosomal AMPARs reconstituted into artificial lipid bilayers from adolescent offspring. Western blot analysis of GluA1- and GluA2-containing AMPAR subunits and the postsynaptic scaffold protein postsynaptic density 95 (PSD95) was conducted to assess protein levels. Results: Prenatal THC exposure decreased AMPAR open-channel probability, reduced mean open time, increased mean closed time, and altered burst channel activity significantly, without altering GluA1, GluA2, or PSD95 protein levels. Furthermore, the interactive channel-gating activity observed in control synaptosomes was absent in synaptosomes derived from THC-exposed offspring. Conclusions: Prenatal cannabinoid exposure induces early alterations in glutamatergic synaptic function primarily mediated by changes in AMPAR channel kinetics rather than receptor abundance. By identifying AMPAR single-channel dysfunction as a sensitive marker of PCE-induced synaptic disruption, this work provides a mechanistic framework linking prenatal THC exposure to long-term alterations in learning and memory.

Polysialic acid (PSA), a highly negatively charged glycan attached mainly to the neural cell adhesion molecule (NCAM), is emerging as a critical but underrecognized extracellular regulator of glutamatergic neurotransmission. While previous literature has focused on PSA’s developmental roles, increasing evidence indicates that PSA–NCAM also contributes to synaptic plasticity mechanisms in the mature brain. This review integrates evidence from structural biophysics, single-channel electrophysiology, and disease models to explain how PSA modulates glutamate receptor gating to control learning and memory. We synthesize findings from biochemical reconstitution, electrophysiological recordings, and in vivo studies to show that PSA can modulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor open probability, burst duration, and cooperative gating without affecting conductance, thereby promoting long-term potentiation. Conversely, PSA selectively suppresses GluN2B-containing extrasynaptic N-methyl D-Aspartate (NMDA) receptor activity by lowering open probability and calcium influx, maintaining an optimal balance between potentiation and depression while providing neuroprotection. Disruption of PSA–NCAM signaling in developmental and disease models, including prenatal cannabinoid exposure and neurodegeneration, produces cognitive deficits reversible by PSA restoration. Notably, much of the current evidence derives from in vitro systems, with relatively few studies conducted in vivo, and studies employing PSA mimetics mostly, which should be considered when interpreting physiological relevance. Collectively, the available evidence suggests that PSA functions as an extracellular modulator linking synaptic glycans to glutamate receptor regulation and plasticity related signaling pathways, highlighting the potential importance of extracellular glycan mechanisms in the control of synaptic function.