Hippocampal Protein Kinase C Signaling Mediates the Short-Term Memory Impairment Induced by Delta9-Tetrahydrocannabinol

Abstract

Cannabis affects cognitive performance through the activation of the endocannabinoid system, and the molecular mechanisms involved in this process are poorly understood. Using the novel object-recognition memory test in mice, we found that the main psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), alters short-term object-recognition memory specifically involving protein kinase C (PKC)-dependent signaling. Indeed, the systemic or intra-hippocampal pre-treatment with the PKC inhibitors prevented the short-term, but not the long-term, memory impairment induced by THC. In contrast, systemic pre-treatment with mammalian target of rapamycin complex 1 inhibitors, known to block the amnesic-like effects of THC on long-term memory, did not modify such a short-term cognitive deficit. Immunoblot analysis revealed a transient increase in PKC signaling activity in the hippocampus after THC treatment. Thus, THC administration induced the phosphorylation of a specific Ser residue in the hydrophobic-motif at the C-terminal tail of several PKC isoforms. This significant immunoreactive band that paralleled cognitive performance did not match in size with the major PKC isoforms expressed in the hippocampus except for PKCθ. Moreover, THC transiently enhanced the phosphorylation of the postsynaptic calmodulin-binding protein neurogranin in a PKC dependent manner. These data demonstrate that THC alters short-term object-recognition memory through hippocampal PKC/neurogranin signaling.

A Hydrolyzed Chicken Extract CMI-168 Enhances Learning and Memory in Middle-Aged Mice

“…However, we did not find differences in the hippocampal neuroplasticity-associated parameters, including LTP induction and maintenance in the hippocampal Schaffer collateral-CA1 pathway, dendritic complexity of the hippocampal CA1 neurons, or changes in expression or phosphorylation levels of hippocampal neuroplasticity-related proteins between the CMI-168 and Chow mice. Among the selected neuroplasticity-related proteins, BDNF-TrkB signaling [17,18], CamKII [19], Erk1/2 [20], PKCζ [21], GluR1 [22], p38 [23], and GSK3 [24] have been linked to the learning and memory functions. SYT-1, SYT-4, and SNAP-25 are members of soluble N -ethylmaleimide-sensitive factor attachment protein receptor located in the presynaptic and postsynaptic regions.…”

Acute Cannabinoids Produce Robust Anxiety-Like and Locomotor Effects in Mice, but Long-Term Consequences Are Age- and Sex-Dependent

“…Using these tasks, preclinical studies have indicated both acute and long-term effects of cannabinoid exposure. Acute THC has been demonstrated to affect object recognition memory in CD-1 mice (Barbieri et al, 2016; Busquets-Garcia et al, 2018), but not in other rodent strains (Ciccocioppo et al, 2002; Long et al, 2010; Swartzwelder et al, 2012; Kasten et al, 2017). It reliably produces anxiogenic and sedative effects at higher doses (Onaivi et al, 1990; Célérier et al, 2006; Schramm-Sapyta et al, 2007; Lee et al, 2015; Kasten et al, 2017).…”

Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Hippocampus: Cannabidiol Blunts Δ9-Tetrahydrocannabinol-Induced Cognitive Impairment

“…Of note, the A2AR/CB1R oligomer would likely result to be relevant for CBD capacity to mitigate the cognitive impairment induced by the psychoactive cannabis derivative  9 -THC in a declarative and spatial memory task. Although other brain areas contribute to the two-object recognition test performance, including perirhinal cortex and striatum [27,37], previous findings reveal a crucial role for hippocampus in the  9 -THC-induced memory impairment [30,31] suggesting this brain areas as the main target for this CBD modulation of A2AR-CB1R interaction. Interestingly, the pre-treatment with the preferentially pre-and post-synaptic A2AR antagonists SCH442416 and KW-6002, respectively [32], demonstrated for the first time that this CBD effect was mostly dependent on the activity of pre-synaptic A2AR receptors.…”

“…To this end, we first assessed the effects of  9 -THC in the two-object recognition test, which evaluates mainly hippocampal-and perirhinal cortex-dependent declarative memory performance [27]. Previous findings indicate that the hippocampus plays a crucial role in the CB1R agonists-induced memory impairment in the two-object recognition test evaluated both in an open field [28] or in a V-maze [29][30][31]. As expected,  9 -THC (3 mg/kg) induced a significant (P < 0.01, Table S1) reduction in the recognition index when administered immediately after training, which was reversed with a pretreatment with the selective CB1R antagonist SR141716A (1 mg/kg) (P < 0.05, Table S1) ( Fig.…”