title: Down-regulation of Homer1b/c protects against chemically induced seizures through inhibition of mTOR signaling.
abstract: 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 S6 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurological Disease, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Ge-Juan
authors.initials: GJ
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Lei
authors.forename: Zheng-Li
authors.initials: ZL
authors.lastname: Di
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D018782:Maze Learning; D051379:Mice; D016716:PC12 Cells; D010433:Pentylenetetrazole / Q000633:toxicity; D010648:Phenylacetates / Q000494:pharmacology; D010766:Phosphorylation; D010852:Picrotoxin / Q000633:toxicity; D034622:RNA Interference; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D005998:Glycine; D000072233:Homer Scaffolding Proteins; D010433:Pentylenetetrazole; D010648:Phenylacetates; D010852:Picrotoxin; D064529:Receptor, Metabotropic Glutamate 5; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C107349:2-chloro-5-hydroxyphenylglycine