Kainic acid-induced status epilepticus decreases mGlu5 receptor and phase-specifically downregulates Homer1b/c expression

Abstract

Globally, over 50 million people are affected by epilepsy, which is characterized by the occurrence of spontaneous recurrent seizures. Almost one-third of the patients show resistance to current anti-epileptic drugs, making the exploration of new molecular targets necessary. An interesting target may be Homer1, due to its diverse roles in epileptogenesis and synaptic plasticity. Indeed, Homer1 regulates group I metabotropic glutamate (mGlu) receptors (i.e. mGlu1 and mGlu5) scaffolding and signaling in neurons. In the present work, using the systemic kainic acid (KA)-induced status epilepticus (SE) model in adult rats, we investigated the mRNA and protein expression patterns of the mGlu5 receptor, Homer1a and Homer1b/c at 10, 80 and 120 days post-SE (i.e. T10, T80 and T120). Epileptogenesis was validated by electrophysiological recordings of seizures via electroencephalography (EEG) monitoring and through upregulation of glial fibrillary acidic protein. At the protein level, the mGlu5 receptor was downregulated in the late latent phase (T10) and the early- and late exponential growth phase (T80 and T120, respectively), which was best observed in the hippocampal CA1 region. At mRNA level, significant downregulation of the mGlu5 receptor was only detected in the late exponential growth phase. Homer1a expression did not change at any investigated time point. Interestingly, Homer1b/c was only downregulated in the late latent phase, a period where spontaneous seizures are extremely rare. Thus, this phase-specific downregulation may be indicative of an endogenous neuroprotective mechanism. In conclusion, these results suggest that Homer1b/c may be an interesting molecular target to prevent epileptogenesis and/or control seizures.