Abstract
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.
Highlights
Temporal lobe epilepsy (TLE) is the most common subtype of epilepsy in human patients (Wiebe, 2000) that results in stereotyped pathological changes including a common aetiology of hippocampal sclerosis
This study initially focused on investigating the effects of CBD on the synaptic and biophysical properties of neurons followed by neuroanatomical investigation in the CA1 hippocampal subfield
To investigate whether CBD alters unitary synaptic events, we first investigated unitary excitatory connections between two pyramidal cells and the inhibition elicited by presynaptic fast spiking (FS), PV and presynaptic adapting CCK cells onto postsynaptic pyramidal cells in the CA1 region of the hippocampus
Summary
Temporal lobe epilepsy (TLE) is the most common subtype of epilepsy in human patients (Wiebe, 2000) that results in stereotyped pathological changes including a common aetiology of hippocampal sclerosis. TLE can be examined in an array of animal TLE models, unlike other human epilepsies (Kandratavicius et al, 2014; Levesque et al, 2016). Factors such as cell death, neurogenesis and neuronal circuit reorganization have been attributed as causes of the disease process (Alexander et al, 2016), as well as a prominent long-standing hypothesis of the primary cause of epilepsy – ion channel abnormalities. Electrophysiological 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. CBD was administered in vivo (100 mg·kgÀ1) at zero time and 90 min post status epilepticus, induced with kainic acid
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