title: Mammalian target of rapamycin complex 1 activation negatively regulates Polo-like kinase 2-mediated homeostatic compensation following neonatal seizures.
abstract: Homeostatic plasticity is characterized by compensatory changes in synaptic strength and intrinsic membrane properties in response to chronic changes in neuronal activity. Neonatal seizures are a naturally occurring source of neuronal overactivation and can lead to long-term epilepsy and cognitive deficits. Using a rodent model of hypoxia-induced neonatal seizures that results in a persistent increase in AMPA receptor (AMPAR) function in hippocampal CA1 pyramidal neurons, we aimed to determine whether there was any evidence of an opposing endogenous homeostatic antiepileptic response. Given that this model results in long-term epilepsy, we also examined mechanisms whereby this homeostasis fails. Whole-cell patch-clamp recordings from neurons in slices removed at intervals following seizure onset revealed an initial up-regulation of AMPAR function that was followed by a transient dynamic attenuation of this enhancement by 48-72 h, although AMPAR function was still increased compared with nonseizure control baseline. This secondary down-regulation of enhanced AMPAR function was coincident with a marked transient increase in expression and function of the Polo-like kinase 2 (PLK2), which has previously been implicated in homeostatic down-regulation of neuronal excitability in cell/slice culture models. The effects were transient and at 1 wk AMPAR function once again became up-regulated, simultaneous with a decrease in PLK2 expression and function. This negative regulation was mediated by subacute postseizure increases in mammalian target of rapamycin (mTOR). Application of the mTOR inhibitor rapamycin prevented post-hypoxic seizure impairment of homeostasis, suggesting that homeostatic plasticity mechanisms may be potentially modifiable therapeutic targets in epileptogenesis.
authors.affiliation: Department of Neurology, Division of Neuroscience, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Sun
authors.forename: Bela
authors.initials: B
authors.lastname: Kosaras
authors.forename: Peter M
authors.initials: PM
authors.lastname: Klein
authors.forename: Frances E
authors.initials: FE
authors.lastname: Jensen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D042282:Microdissection; D046912:Multiprotein Complexes; D009473:Neuronal Plasticity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000378:metabolism; D012640:Seizures / Q000378:metabolism* / Q000473:pathology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D000900:Anti-Bacterial Agents; D046912:Multiprotein Complexes; D011506:Proteins; D018091:Receptors, AMPA; C546845:mTOR protein, rat; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C530504:Plk2 protein, rat; D020123:Sirolimus