Differential effects of AMPA receptor inhibition on seizure-like events in murine and human brain slices

Epilepsy is a frequent neurological condition with a worldwide prevalence of 0.5-1%. Current therapies are limited by adverse effects as well as drug resistance. This highlights the need for novel, target-specific antiseizure medications with improved efficacy and fewer side effects. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors represent a therapeutic target as demonstrated by perampanel, an AMPA receptor antagonist used clinically as antiseizure medication. AMPA receptors typically mediate fast excitatory neurotransmission. Their properties are modulated by auxiliary proteins that can alter receptor activation, deactivation and desensitization, including converting them into slow AMPA receptors. In this study, we tested different AMPA receptor inhibitors, including perampanel, for their ability to suppress seizure-like events (SLE). SLE were recorded with extracellular electrodes in cortical brain slices from healthy mice and from epilepsy patients who underwent resective surgery. SLE were induced with 4-aminopyridine (4-AP) or a combination of 4-AP and high-potassium. We found that seizure-like events in murine tissue appeared more frequently, with higher amplitude and spike frequency, but were briefer than in human tissue. GYKI53655, NBQX and perampanel were equally effective in inhibiting SLE in murine und human brain slices. In contrast, the antagonist LY3130481, specific for the AMPA receptor auxiliary protein γ-8, showed only weak efficacy in murine tissue, but blocked of SLE in human tissue almost completely. The species-specific differences we found for LY3130481 highlight the benefit of using human tissue in preclinical research and underline that auxiliary subunits remain a promising therapeutic target for the development of new antiseizure medications.