Analysis in conditional cannabinoid 1 receptor-knockout mice reveals neuronal subpopulation-specific effects on epileptogenesis in the kindling paradigm

Rüden, Eva Lotta von; Jafari, Mehrnoosh; Bogdanovic, R.M.; Wotjak, Carsten T.; Potschka, Heidrun

doi:10.1016/j.nbd.2014.08.001

Cited by 44 publications

(40 citation statements)

References 71 publications

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“…Agonism of human http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=507 expressed in HEK293 cells by CBD has been popularly reported with different potencies (3–10 μm) (Bisogno et al, 2001; De Petrocellis et al, 2011). The existing literature surrounding the role of TRPV1 in epilepsy is conflicted between different studies which indicate that activation of TRPV1 has no involvement (von Ruden et al, 2015), a proconvulsant (Manna and Umathe, 2012) or an anticonvulsant (Chen et al, 2013; Gonzalez‐Reyes et al, 2013) effect in epilepsy. Whether CBD is directly modulating http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=75 or targeting a novel postsynaptic cannabinoid receptor or alternatively working in synchrony with other previously established targets, for example, GRP55 or TRPV receptors (De Petrocellis et al, 2011; 2012; Hill et al, 2012b; Iannotti et al, 2014), remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Khan

Shekh‐Ahmad²,

Khalil³

et al. 2018

British J Pharmacology

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Background and PurposeA non‐psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy. To elucidate the mechanisms by which CBD exerts its anti‐seizure effects, we investigated its effects at synaptic connections and on the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin (PV)‐expressing and adapting, cholecystokinin (CCK)‐expressing interneurons. We also investigated whether in vivo treatment with CBD altered the fate of CCK and PV interneurons using immunohistochemistry.Experimental ApproachElectrophysiological intracellular whole‐cell recordings combined with neuroanatomy were performed in acute brain slices of rat temporal lobe epilepsy in in vivo (induced by kainic acid) and in vitro (induced by Mg2+‐free solution) epileptic seizure models. For immunohistochemistry experiments, CBD was administered in vivo (100 mg·kg−1) at zero time and 90 min post status epilepticus, induced with kainic acid.Key ResultsBath application of CBD (10 μM) dampened excitability at unitary synapses between pyramidal cells but enhanced inhibitory synaptic potentials elicited by fast spiking and adapting interneurons at postsynaptic pyramidal cells. Furthermore, CBD restored impaired membrane excitability of PV, CCK and pyramidal cells in a cell type‐specific manner. These neuroprotective effects of CBD were corroborated by immunohistochemistry experiments that revealed a significant reduction in atrophy and death of PV‐ and CCK‐expressing interneurons after CBD treatment.Conclusions and ImplicationsOur data suggest that CBD restores excitability and morphological impairments in epileptic models to pre‐epilepsy control levels through multiple mechanisms to reinstate normal network function.

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Section: Discussionmentioning

confidence: 99%

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Khan

Shekh‐Ahmad²,

Khalil³

et al. 2018

British J Pharmacology

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“…A similar pattern has been found in macaques [22], mice [20] and rats [19], where the highest CB 1 density was found within the molecular layer of the dentate gyrus, while the granule cell layer appeared to be completely devoid of CB 1 immunoreactivity. In immunohistochemical studies made in rats [19], mice [20, 57] and macaques [22] strong immunoreactivity occurred in the Cornu Ammonis (CA) regions of the hippocampus within the pyramidal layer. Interestingly, the cell bodies of pyramidal neurons in CA1-CA3 fields appeared to be unstained but surrounded by a dense plexus of highly immunoreactive fibres [19–22, 57].…”

Section: Discussionmentioning

confidence: 99%

“…In immunohistochemical studies made in rats [19], mice [20, 57] and macaques [22] strong immunoreactivity occurred in the Cornu Ammonis (CA) regions of the hippocampus within the pyramidal layer. Interestingly, the cell bodies of pyramidal neurons in CA1-CA3 fields appeared to be unstained but surrounded by a dense plexus of highly immunoreactive fibres [19–22, 57]. Indeed, we found strong CB 1 immunostaining associated with a dense network of fibres in the stratum pyramidale also surrounding immunonegative pyramidal neuronal bodies.…”

Section: Discussionmentioning

confidence: 99%

“…In rats [58] and humans [37] most of CB 1 immunoreactive neurons in the hippocampus are GABAergic, and are involved in mechanism by which cannabinoids impair memory and associational processes [37]. Expression of CB 1 is markedly increased specially in the stratum pyramidale (CA1-CA3) and molecular layer of the dentate gyrus in different mouse models of epilepsy [57, 59, 60] and human patients with epilepsy [60]. This CB 1 upregulation may be a compensatory mechanism of excitatory neurons to strengthen the negative feedback loop of the endocannabinoid system and to down-regulate neurotransmitter release [57].…”

Section: Discussionmentioning

confidence: 99%

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Spatial distribution of cannabinoid receptor type 1 (CB1) in normal canine central and peripheral nervous system

et al. 2017

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The endocannabinoid system is a regulatory pathway consisting of two main types of cannabinoid receptors (CB1 and CB2) and their endogenous ligands, the endocannabinoids. The CB1 receptor is highly expressed in the central and peripheral nervous systems (PNS) in mammalians and is involved in neuromodulatory functions. Since endocannabinoids were shown to be elevated in cerebrospinal fluid of epileptic dogs, knowledge about the species specific CB receptor expression in the nervous system is required. Therefore, we assessed the spatial distribution of CB1 receptors in the normal canine CNS and PNS. Immunohistochemistry of several regions of the brain, spinal cord and peripheral nerves from a healthy four-week-old puppy, three six-month-old dogs, and one ten-year-old dog revealed strong dot-like immunoreactivity in the neuropil of the cerebral cortex, Cornu Ammonis (CA) and dentate gyrus of the hippocampus, midbrain, cerebellum, medulla oblongata and grey matter of the spinal cord. Dense CB1 expression was found in fibres of the globus pallidus and substantia nigra surrounding immunonegative neurons. Astrocytes were constantly positive in all examined regions. CB1 labelled neurons and satellite cells of the dorsal root ganglia, and myelinating Schwann cells in the PNS. These results demonstrate for the first time the spatial distribution of CB1 receptors in the healthy canine CNS and PNS. These results can be used as a basis for further studies aiming to elucidate the physiological consequences of this particular anatomical and cellular distribution.

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“…However, since FS-BC inputs tend to depress during sustained activation (Hefft and Jonas, 2005), as would occur during seizures, facilitating asynchronous inhibition from AC-INs is likely to significantly limit principal cell activity during seizures. In this regard, genetic deletion of CB 1 R in inhibitory neurons reduces the duration of after-discharges following kindling (von Ruden et al, 2014), indicating a role for CB 1 R-sensitive inhibition in seizure termination. The identification of increased CB 1 R availability in spatial and temporal proximity to seizure initiation zone in epileptic patients (Goffin et al, 2011) together with our demonstration of enhanced CB 1 R-sensitive AC-IN inhibition, is consistent with the proposal that upregulation of interneuronal CB 1 R may predispose to development of an epileptogenic zone (Goffin et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Dentate cannabinoid-sensitive interneurons undergo unique and selective strengthening of mutual synaptic inhibition in experimental epilepsy

Swietek

Proddutur

et al. 2016

Neurobiology of Disease

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Altered inhibition is a salient feature of hippocampal network reorganization in epilepsy. Hippocampal pyramidal cells and dentate granule cells show specific reduction in cannabinoid receptor type 1 (CB1R)-sensitive GABAergic inputs in experimental epilepsy. In the dentate gyrus, CB1Rs regulate synaptic release from accommodating interneurons (AC-INs) with adapting firing characteristics and axonal projections in the molecular layer, but not from fast-spiking basket cells (FS-BCs). However, it is not known whether the intrinsic physiology and synaptic inhibition of AC-INs responsible for CB1R-sensitive inhibition is altered in epilepsy. Using the pilocarpine-induced status epilepticus (SE) model of epilepsy, we find that the basic physiological characteristics of AC-INs in epileptic rats are not different from age-matched controls. In paired interneuronal recordings, the amplitude of unitary inhibitory synaptic currents (uIPSCs) between AC-INs doubled after SE. Non-stationary noise analysis revealed that the post-SE strengthening of synapses between AC-INs resulted from an increase in postsynaptic receptors. Baseline synaptic release and CB1R antagonist enhancement of release at synapses between AC-INs were not different between control and post-SE rats. Additionally, uIPSC amplitude in FS-BCs to AC-INs pairs was unchanged after SE indicating input-specific microcircuit alterations in inhibitory inputs to AC-INs. At the network level, AC-INs showed no reduction in spontaneous and miniature inhibitory synaptic current (sIPSC or mIPSC) frequency or amplitude after SE. However, AC-IN mIPSC amplitude was persistently enhanced in post-SE and epileptic rats. CB1R agonist reduced the amplitude and suppressed a greater proportion of sIPSCs in AC-INs from post-SE and epileptic rats demonstrating a novel, cell-type specific increase in CB1R-sensitive inhibition of AC-INs after SE. This unique post-SE strengthening of inhibition between AC-INs could lead to activity-dependent suppression of AC-IN firing and compromise dentate CB1R-sensitive inhibition in epilepsy.

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Analysis in conditional cannabinoid 1 receptor-knockout mice reveals neuronal subpopulation-specific effects on epileptogenesis in the kindling paradigm

Cited by 44 publications

References 71 publications

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Spatial distribution of cannabinoid receptor type 1 (CB1) in normal canine central and peripheral nervous system

Dentate cannabinoid-sensitive interneurons undergo unique and selective strengthening of mutual synaptic inhibition in experimental epilepsy

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