title: Dentate cannabinoid-sensitive interneurons undergo unique and selective strengthening of mutual synaptic inhibition in experimental epilepsy.
abstract: 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.
authors.affiliation: Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, PR China; Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Bogumila
authors.initials: B
authors.lastname: Swietek
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Proddutur
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ 07103, USA. Electronic address: santhavi@njms.rutgers.edu.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Santhakumar
mesh_terms: D000200:Action Potentials; D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology*; D053444:Inhibitory Postsynaptic Potentials; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010862:Pilocarpine; D010880:Piperidines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000503:physiopathology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D010862:Pilocarpine; C103505:AM 251
keywords: Cannabinoid; Dentate gyrus; Epilepsy; GABA; Interneuron; Seizure