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α‐Amino‐3‐Hydroxy‐5‐Methyl‐4‐Isoxazolepropionic Acid Receptor Plasticity Sustains Severe, Fatal Status Epilepticus
Author(s) -
Adotevi Nadia,
Lewczuk Ewa,
Sun Huayu,
Joshi Suchitra,
Dabrowska Natalia,
Shan Sarah,
Williamson John,
Kapur Jaideep
Publication year - 2020
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25635
Subject(s) - status epilepticus , ampa receptor , neuroscience , glutamatergic , hippocampal formation , glutamate receptor , medicine , neurotransmission , excitatory postsynaptic potential , synaptic plasticity , epilepsy , anesthesia , pharmacology , inhibitory postsynaptic potential , receptor , biology
Objective Generalized convulsive status epilepticus is associated with high mortality. We tested whether α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor plasticity plays a role in sustaining seizures, seizure generalization, and mortality observed during focal onset status epilepticus. We also determined whether modified AMPA receptors generated during status epilepticus could be targeted with a drug. Methods Electrically induced status epilepticus was characterized by electroencephalogram and behavior in GluA1 knockout mice and in transgenic mice with selective knockdown of the GluA1 subunit in hippocampal principal neurons. Excitatory and inhibitory synaptic transmission in CA1 neurons was studied using patch clamp electrophysiology. The dose response of N,N,H ,‐trimethyl‐5‐([tricyclo(3.3.1.13,7)dec‐1‐ylmethyl]amino)‐1‐pentanaminiumbromide hydrobromide (IEM‐1460), a calcium‐permeable AMPA receptor antagonist, was determined. Results Global removal of the GluA1 subunit did not affect seizure susceptibility; however, it reduced susceptibility to status epilepticus. GluA1 subunit knockout also reduced mortality, severity, and duration of status epilepticus. Absence of the GluA1 subunit prevented enhancement of glutamatergic synaptic transmission associated with status epilepticus; however, γ‐aminobutyric acidergic synaptic inhibition was compromised. Selective removal of the GluA1 subunit from hippocampal principal neurons also reduced mortality, severity, and duration of status epilepticus. IEM‐1460 rapidly terminated status epilepticus in a dose‐dependent manner. Interpretation AMPA receptor plasticity mediated by the GluA1 subunit plays a critical role in sustaining and amplifying seizure activity and contributes to mortality. Calcium‐permeable AMPA receptors modified during status epilepticus can be inhibited to terminate status epilepticus. ANN NEUROL 2020;87:84–96