Cannabinoid receptors are widely expressed throughout the hippocampal formation, but are particularly dense in the dentate gyrus (DG) subregion. We, and others, have shown in mice that cannabinoid type 1 receptors (CB1Rs) are involved in a long-term depression (LTD) that can be induced by prolonged 10 Hz stimulation of the medial perforant path (MPP)-granule cell synaptic input to the DG. Here, we extend this work to examine the involvement of CB1Rs in other common forms of LTD in the hippocampus of juvenile male and female Sprague–Dawley rats (Rattus norvegicus). We found, as in mice, that prolonged 10 Hz stimulation (6000 pulses) could reliably induce a form of LTD that was dependent upon CB1R activation. In addition, we also discovered a role for both CB1R and mGluR proteins in LTD induced with 1 Hz low-frequency stimulation (1 Hz-LTD; 900 pulses) and in LTD induced by bath application of the group I mGluR agonist (RS)-3,5-Dihydroxyphenylglycine (DHPG; DHPG-LTD). This study elucidates an essential role for endocannabinoid receptors in a number of forms of LTD in the rat DG, and identifies a novel role for CB1Rs as potential therapeutic targets for conditions that involve impaired LTD in the DG.

Choline is an essential nutrient that is being explored as a nutritional treatment for many neurological disorders. Indeed, choline has already moved to being used in clinical trials for Fetal Alcohol Spectrum Disorders (FASD), and there is increased pressure to better understand its therapeutic mechanism(s) of action. This is particularly true given its potential to directly effect synaptic mechanisms that are believed important for cognitive processes. In the current work we study how the direct application of choline can affect synaptic transmission in hippocampal slices obtained from adolescent (post-natal days 21-28) Sprague-Dawley rats (Rattus norvegicus). The acute administration of choline chloride (2 mM) reliably induced a long-term depression (LTD) of field excitatory postsynaptic potentials (fEPSP) in the DG in vitro. The depression required the involvement of M1-receptors, and the magnitude of the effect was similar in slices obtained from male and female animals. To further study the impact of choline in an animal model of FASD, we examined offspring from dams fed an ethanol-containing diet (35.5% ethanol-derived calories) throughout gestation. In slices from the adolescent animals that experienced prenatal ethanol exposure (PNEE), we found that the choline induced an LTD that uniquely involved the activation of NMDA and M1 receptors. This study provides a novel insight into how choline can modulate hippocampal transmission at the level of the synapse and that it can have unique effects following PNEE.

Prenatal ethanol exposure (PNEE) is a leading cause of neurodevelopmental impairments, yet treatments for individuals with PNEE are limited. Importantly, postnatal supplementation with the essential nutrient choline can attenuate some adverse effects of PNEE on cognitive development; however, the mechanisms of action for choline supplementation remain unclear. This study used an animal model to determine if choline supplementation could restore hippocampal synaptic plasticity that is normally impaired by prenatal alcohol. Throughout gestation, pregnant Sprague Dawley rats were fed an ethanol liquid diet (35.5% ethanol-derived calories). Offspring were injected with choline chloride (100 mg/kg/day) from postnatal days (PD) 10–30, and then used for in vitro electrophysiology experiments as juveniles (PD 31–35). High-frequency conditioning stimuli were used to induce long-term potentiation (LTP) in the medial perforant path input to the dentate gyrus of the hippocampus. PNEE altered synaptic transmission in female offspring by increasing excitability, an effect that was mitigated with choline supplementation. In contrast, PNEE juvenile males had decreased LTP compared to controls, and this was rescued by choline supplementation. These data demonstrate sex-specific changes in plasticity following PNEE, and provide evidence that choline-related improvements in cognitive functioning may be due to its positive impact on hippocampal synaptic physiology.

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