Endocannabinoid receptors contribute significantly to multiple forms of long-term depression in the rat dentate gyrus

Fontaine, Christine J.; Gräfe, Erin L.; Pinar, Cristina; Río, Itziar Bonilla‐Del; Grandes, Pedro; Christie, Brian R.

doi:10.1101/lm.050666.119

Cited by 14 publications

(16 citation statements)

References 77 publications

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“…Significantly, the functional consequences of this difference remain to be determined. Our results indicate that eCBs and CB 1 Rs are involved in the induction of these two different forms of t-LTD, in agreement with previous field recordings showing that the eCB system is involved in synaptic plasticity at PP-DG synapses (Wang et al, 2016; Peñasco et al, 2019; Fontaine et al, 2020). Here we did not elucidate the location of the CB 1 Rs mediating t-LTD, such that further work will be required to address this question.…”

Section: Discussionsupporting

confidence: 93%

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses

Martínez-Gallego,

Coatl-Cuaya,

Rodríguez-Moreno

2024

Preprint

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The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic, and sensory and information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirement. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

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Section: Discussionsupporting

confidence: 93%

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses

Martínez-Gallego,

Coatl-Cuaya,

Rodríguez-Moreno

2024

Preprint

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“…The CB1 receptor is also implicated in neuroinflammation, and so this dissertation touches on microglia (3,4). Finally, the CB1 receptor is implicated in hippocampal synaptic plasticity, and so long-term depression is assayed (5,6). Together these results show that prenatal cannabis exposure has long-lasting, sex-dependent effects in the rat hippocampus.…”

Section: Introduction 11 Prefacementioning

confidence: 93%

Assessing Changes in Synaptic Plasticity Using an Awake Closed-Head Injury Model of Mild Traumatic Brain Injury

Christie

Gross

Willoughby

et al. 2023

JoVE

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Prenatal cannabis exposure is as common as prenatal alcohol exposure, and yet it is understudied. With the recent legalization of cannabis, it is doubly important to elucidate these effects. The hippocampus is rich in cannabinoid type 1 receptors, which are targeted by the psychoactive component of cannabis. The hippocampus is central to learning and memory and is known to be affected acutely by this drug. In this dissertation, I examine how prenatal THC exposure affects different populations of hippocampal interneurons, how morphological characteristics of microglia are altered, and hippocampal synaptic plasticity is affected, and how inhibitory and excitatory markers My findings show not only that there are alterations in all these areas, but that there are regional and sex differences in many of these changes. These results suggest that there is increased GABAA recruitment via increased gephyrin cluster sizes. In absence of other receptor changes this shows that the balance of inhibition and excitation is shifted towards inhibition. Dendritic spines decreases are consistent with human clinical findings with similar psychiatric outcomes. As interneuron densities are static compared with other outcome measures, early perturbations in the endocannabinoid system likely drive the observed interneuron alterations, which then drive spine, receptor, and plasticity alterations. This work shows that there are consequences of prenatal cannabis exposure into adulthood.

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“…In a subset of experiments focused on the MPP -DG synapse from control and MK-801-treated slices, WIN 55,212-2, a CB 1 R agonist (WIN, 5 μM), was bath perfused for 15 minutes to examine the presynaptic induction of LTD mediated by CB 1 receptor activation, as previously reported (Fontaine et al, 2020). Additionally, physostigmine (10 μM), an acetylcholinesterase inhibitor, was perfused for 15 min to evaluate endogenous 2-AG production in the MPP -DG synapse, as previously demonstrated in acute hippocampal slices (Wang et al, 2018b(Wang et al, , 2018a.…”

Section: Pharmacological Modulation Of 2-ag Signaling Pathwaymentioning

confidence: 99%

“…Additionally, multiple works have shown the relevance of the cannabinoid 1 receptor (CB 1 R) for the induction of long-term depression and potentiation in the PP -DG synapses (Wu et al, 2006;Wang et al, 2016Wang et al, , 2018bPeñasco et al, 2019;Fontaine et al, 2020). Interestingly, dysregulation of NMDARs and CB 1 R is present in animal models and schizophrenic individuals (Szűcs et al, 2016;Forsyth and Lewis, 2017;Osborne et al, 2019;Márquez et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Neonatal hypofunction of NMDA receptors alters perforant path synaptic plasticity, filtering and impairs dentate gyrus-mediated spatial discrimination

Márquez,

Lopez-Rubalcava,

Galvan

2023

Preprint

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Background and Purpose: Transient hypofunction of NMDARs represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant path synapses, have barely been explored in this pathological condition. Experimental Approach: We identified a series of synaptic alterations of the lateral and medial perforant paths, in animals neonatally treated with the NMDAR antagonist MK-801. The dysregulation here reported suggests decreased cognitive performance, for which the dentate gyrus is critical. Key Results: We identified alterations in the synaptic properties of the lateral and medial perforant paths to the dentate gyrus synapses in MK-801-treated animals. Altered glutamate release and decreased synaptic strength precede an impairment in the induction and expression of LTP and cannabinoid 1 receptor (CB1R)-mediated LTD. Remarkably, by inhibiting the degradation of 2-arachidonoylglycerol, the endogenous ligand of the CB1R, we restored the LTD in animals treated with MK-801. Additionally, we show for the first time that spatial discrimination, a cognitive task that requires dentate gyrus integrity, is impaired in animals exposed to transient hypofunction of NMDARs. Conclusion and Implications: Descriptive and mechanistic evidence showing the dysregulation of glutamatergic transmission and synaptic plasticity from the entorhinal cortex to the dentate gyrus is presented. These findings may explain the cellular dysregulations underlying the altered cognitive processing in the dentate gyrus associated with schizophrenia.

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Endocannabinoid receptors contribute significantly to multiple forms of long-term depression in the rat dentate gyrus

Cited by 14 publications

References 77 publications

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses

Assessing Changes in Synaptic Plasticity Using an Awake Closed-Head Injury Model of Mild Traumatic Brain Injury

Neonatal hypofunction of NMDA receptors alters perforant path synaptic plasticity, filtering and impairs dentate gyrus-mediated spatial discrimination

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