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Title: The effect of the phytocannabinoid cannabidivarin (CBDV) on synaptic transmission in a model of epilepsy
Author: Hill , Charlotte Louise
ISNI:       0000 0004 6352 2316
Awarding Body: University of Reading
Current Institution: University of Reading
Date of Award: 2016
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Epilepsy affects 50 million people worldwide and is characterised by spontaneous recurring seizures. Current anti-epileptic drugs (AEDs) control seizure activity, but are neither preventative nor curative. However, approximately one in three people with epilepsy do not have their seizures adequately controlled with currently available AEDs. Therefore, ongoing research into novel AEDs is still warranted. Research conducted at the University of Reading has demonstrated the non-psychoactive phytocannabinoids cannabidiol (CBD) and cannabidivarin (CBDV) to exert significant anti-epileptiform and anticonvulsant properties in vitro and in vivo. However, the mechanism/s by which CBD and CBDV mediate these effects are currently unknown. The aims of this research were to investigate the effects of CBD, and primarily CBDV, on synaptic transmission using extracellular and intracellular electrophysiological techniques in normal, healthy brain tissue and brain tissue from a rat model of temporal lobe epilepsy. Acute transverse hippocampal slices were taken from young (P24-28) control rats, rats with epilepsy (~P50-60) and age-matched (~P50-60) non-epileptic control rats. Pairs of evoked local field potentials were recorded from the CA1 region using multi-electrode arrays and the paired pulse ratio (PPR) was obtained. Whole cell patch clamp of CA1 pyramidal cells was used to record miniature and spontaneous inhibitory postsynaptic currents (mIPSCs and sIPSCs, respectively). Cumulative concentrations of CBD and CBDV significantly reduced the PPR in hippocampal slices from control rats and cumulative concentrations of CBDV significantly reduced the PPR in hippocampal slices from rats confirmed to have epilepsy. The effect of cumulative concentrations of CBDV on PPR in hippocampal slices from rats with epilepsy was stronger than that observed in slices from P50-60 control rats, as CBDV reduced the PPR across a greater range of inter-stimulus intervals. In hippocampal slices from CBDV-treated rats with epilepsy, application of acute CBDV was more effective at reducing the PPR across a wider range of inter­stimulus intervals and suggests that chronic treatment with CBDV may 'unmask' the effect of acute CBDV. In hippocampal slices from rats with epilepsy, mIPSC frequency was significantly reduced and indicates a deficit in the presynaptic quantal release of GABA neurotransmitter in the CA1 region. CBDV had no effect on mIPSC amplitude or frequency in hippocampal slices from both P24-28 control rats and rats with epilepsy, CBDV significantly reduced sIPSC frequency without affecting sIPSC amplitude in hippocampal slices from control rats. However, in hippocampal slices from rats with epilepsy, CBDV had no effect on sIPSC amplitude or frequency. The results of the patch clamp experiments are consistent with CBDV decreasing action potential-dependent presynaptic release of GABA from inhibitory interneurones in hippocampal slices from control rats, but not in rats with epilepsy. In conclusion, CBD and CBDV alter synaptic transmission in the CA1 region of the hippocampus to enhance glutamatergic signalling via a mechanism that is likely to be presynaptic in origin and may involve the modulation of [Ca2+] and a change in release probability of neurotransmitter. The effect of CBDV on the PPR was similar in hippocampal slices from both epileptic and non­epileptic rats, which suggests a common mechanism to alter synaptic transmission in both tissues. In addition, chronic CBDV-treatment may also increase the effectiveness of the mechanism by which CBDV reduces the PPR in hippocampal tissue from rats confirmed to have epilepsy. Finally, epilepsy altered inhibitory neurotransmission in the CA1 area, which is likely to be due to the reduction in quanta! release of GABA from interneurones that synapse onto CA1 pyramidal neurones. CBDV may have a disease-dependent effect on inhibitory neurotransmission in hippocampus CA1, as CBDV reduced the action-potential-dependent release of GABA in tissue from control rats, but had no effect in tissue from epileptic rats.
Supervisor: Stephens, Gary J. ; Williams, Claire M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available