Essential roles of Homer-1a in homeostatic regulation of pyramidal cell excitability: a possible link to clinical benefits of electroconvulsive shock

Homer‐1a/Vesl1S, a member of the scaffold protein family Homer/Vesl, is expressed during seizure and serves to reduce seizure susceptibility. Cellular mechanisms for this feedback regulation were studied in neocortex pyramidal cells by injecting Homer‐1a protein intracellularly. The injection reduced membrane excitability as demonstrated in two ways. First, the resting potential was hyperpolarized by 5–10 mV. Second, the mean frequency of spikes evoked by depolarizing current injection was decreased. This reduction of excitability was prevented by applying each of the followings: the calcium chelator BAPTA, the calcium store depletor cyclopiazonic acid (CPA), the insitol‐1,4,5‐trisphosphate receptor (IP3R) blocker heparin, the phospholipase C (PLC) inhibitor U‐73122, the metabotropic glutamate receptor (mGluR) antagonist 2‐methyl‐6‐(phenylethynyl)‐pyridine (MPEP), and the large‐conductance calcium activated potassium channel (BK channel) antagonist charybdotoxin. The small‐conductance calcium activated potassium channel (SK channel) blocker dequalinium was ineffective. These findings suggest that activation of mGluR by Homer‐1a produced IP3, which caused inositol‐induced calcium release and a consequent BK channel opening, thus hyperpolarizing the injected neurons. In slices from rats subjected to electroconvulsive shock (ECS), a comparable reduction of excitability was observed without Homer‐1a injection. The ECS‐induced reduction of excitability was abolished by MPEP, charybdotoxin, heparin or BAPTA. Intracellular injection of anti‐Homer‐1a antibody was suppressive as well, but anti‐Homer‐1b/c antibody was not. We propose that ECS‐induced Homer‐1a stimulated the same pathway as did the injected Homer‐1a, thereby driving a feedback regulation of excitability.