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Purinergic control of hippocampal circuit hyperexcitability in D ravet syndrome
Author(s) -
Gu Feng,
Hazra Anupam,
Aulakh Ahmad,
Žiburkus Jokūbas
Publication year - 2014
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12487
Subject(s) - neuroscience , hippocampal formation , hippocampus , medicine , agonist , epilepsy , adenosine , endocrinology , psychology , receptor
Summary Objective Severe myoclonic epilepsy in infancy ( SMEI ) or D ravet syndrome is one of the most devastating childhood epilepsies. Children with SMEI have febrile and afebrile seizures ( FS and a FS ), 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 (m SMEI ), we studied hippocampal cell and circuit excitability, particularly during hyperthermia, and tested whether an adenosine A 1 receptor ( A 1 R ) 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 ( FSLE s) in juvenile mouse hippocampal slices. We used hyperthermia to elicit FSLE s in hippocampal slices, while making use of adenosine A 1 R agonist N 6‐cyclopentyladenosine ( CPA ) to control abnormally widespread neural activity and FSLE s. Results We discovered a significant excitation/inhibition ( E / I ) imbalance in m SMEI 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 n m ) of CPA blocked FSLE s and reduced the spatial extent of abnormal neural activity spread while preserving basal levels of excitatory synaptic transmission. Significance Our study reveals significant hippocampal synapse and circuit dysfunctions in m SMEI and demonstrates that the A 1 R agonist CPA can reliably control hippocampal hyperexcitability and FSLE s in vitro. These findings may warrant further investigations of purinergic agonists as part of the development of new therapeutic approaches for D ravet syndrome.