Background:　Homer　is　a　family　of　post　synaptic　density　proteins　functionally　and　physically　attached　to　target　proteins　at　proline-rich　sequences.　Reducing　Homer1b/c　expression　has　been　shown　in　previous　studies　to　be　protective　against　excitotoxic　insults,　implicating　Homer1b/c　in　the　physiological　regulation　of　aberrant　neuronal　excitability.　Methods:　To　test　the　efficacy　of　a　Homer1b/c　reducing　therapy　for　disorders　with　a　detrimental　hyperexcitability　profile　in　mice,　we　used　small　interfere　RNA　(siRNA)　to　decrease　endogenous　Homer1b/c　expression　in　mouse　hippocampus.　The　baseline　motor　and　cognitive　behavior　was　measured　by　sensorimotor　tests,　Morris　water　maze　and　elevated　plus　maze　tasks.　The　anti-epileptic　effects　of　Homer1b/c　knockdown　were　determined　in　two　chemically　induced　seizure　models　induced　by　Picrotoxin　(PTX)　or　pentylenetetrazole　(PTZ)　administration.　Results:　The　results　of　sensorimotor　tests,　Morris　water　maze　and　elevated　plus　maze　tasks　showed　that　Homer1b/c　reduction　had　no　effect　on　baseline　motor　or　cognitive　behavior.　In　two　chemically　induced　seizure　models,　mice　with　reduced　Homerb/c　protein　had　less　severe　seizures　than　control　mice.　Total　Homer1b/c　protein　levels　and　seizure　severity　were　highly　correlated,　such　that　those　mice　with　the　most　severe　seizures　also　had　the　highest　levels　of　Homer1b/c.　In　addition,　the　phosphorylation　of　mammalian　target　of　rapamycin　(mTOR)　and　its　target　protein　56　was　significantly　inhibited　in　Homer1b/c　down-regulated　mice.　Homer1b/c　knockdown-induced　inhibition　of　mTOR　pathway　was　partially　ablated　by　the　metabotropic　glutamate　receptor　5　(mGluR5)　agonist　CHPG.　Conclusion:　Our　results　demonstrate　that　endogenous　Homer1b/c　is　integral　for　regulating　neuronal　hyperexcitability　in　adult　animals　and　suggest　that　reduction　of　Homer1b/c　could　protect　against　chemically　induced　seizures　through　inhibition　mTOR　pathway.　Copyright　(C)　2015　S　Karger　AG,　Basel