title: Purinergic control of hippocampal circuit hyperexcitability in Dravet syndrome.
abstract: OBJECTIVE
  Severe myoclonic epilepsy in infancy (SMEI) or Dravet syndrome is one of the most devastating childhood epilepsies. Children with SMEI have febrile and afebrile seizures (FS and aFS), ataxia, and social and cognitive dysfunctions. SMEI is pharmacologically intractable and can be fatal in 10-20% of patients. It remains to be elucidated how channelopathies that cause SMEI impact synaptic activities in key neural circuits, and there is an ongoing critical need for alternative methods of controlling seizures in SMEI. Using the SCN1A gene knock-in mouse model of SMEI (mSMEI), we studied hippocampal cell and circuit excitability, particularly during hyperthermia, and tested whether an adenosine A1 receptor (A1R) agonist can reliably control hippocampal circuit hyperexcitability.
  
  
  METHODS
  Using a combination of electrophysiology (extracellular and whole-cell voltage clamp) and fast voltage-sensitive dye imaging (VSDI), we quantified synaptic excitation and inhibition, spatiotemporal characteristics of neural circuit activity, and hyperthermia-induced febrile seizure-like events (FSLEs) in juvenile mouse hippocampal slices. We used hyperthermia to elicit FSLEs in hippocampal slices, while making use of adenosine A1R agonist N6-cyclopentyladenosine (CPA) to control abnormally widespread neural activity and FSLEs.
  
  
  RESULTS
  We discovered a significant excitation/inhibition (E/I) imbalance in mSMEI hippocampi, in which inhibition was decreased and excitation increased. This imbalance was associated with an increased spatial extent of evoked neural circuit activation and a lowered FSLE threshold. We found that a low concentration (50 nm) of CPA blocked FSLEs and reduced the spatial extent of abnormal neural activity spread while preserving basal levels of excitatory synaptic transmission.
  
  
  CONCLUSIONS
  Our study reveals significant hippocampal synapse and circuit dysfunctions in mSMEI and demonstrates that the A1R agonist CPA can reliably control hippocampal hyperexcitability and FSLEs in vitro. These findings may warrant further investigations of purinergic agonists as part of the development of new therapeutic approaches for Dravet syndrome.
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas, U.S.A.
authors.forename: Feng
authors.initials: F
authors.lastname: Gu
authors.forename: Anupam
authors.initials: A
authors.lastname: Hazra
authors.forename: Ahmad
authors.initials: A
authors.lastname: Aulakh
authors.forename: Jokūbas
authors.initials: J
authors.lastname: Žiburkus
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D058906:Purinergic P1 Receptor Agonists; C568249:Scn1a protein, mouse; C048599:N(6)-cyclopentyladenosine; D000241:Adenosine
keywords: Adenosine A1 receptor; Dravet syndrome; Hyperthermia; Imaging; SCN1A gene; Seizure