title: Short-term treatment with the GABAA receptor antagonist pentylenetetrazole produces a sustained pro-cognitive benefit in a mouse model of Down's syndrome.
abstract: OBJECTIVE
  Down's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normalized by low doses of GABAA receptor antagonists in adult animals. In this study, we explore the therapeutic potential of pentylenetetrazole, a GABAA receptor antagonist with a history of safe use in humans.
  
  
  METHODS
  Long-term memory was assessed by the novel object recognition test in different cohorts of TS mice after a delay following a short-term chronic treatment with pentylenetetrazole. Seizure susceptibility, an index of treatment safety, was studied by means of EEG, behaviour and hippocampus morphology. EEG spectral analysis was used as a bio-marker of the treatment.
  
  
  RESULTS
  PTZ has a wide therapeutic window (0.03-3 mg·kg(-1)) that is >10-1000-fold below its seizure threshold and chronic pentylenetetrazole treatment did not lower the seizure threshold. Short-term, low, chronic dose regimens of pentylenetetrazole elicited long-lasting (>1 week) normalization of cognitive function in young and aged mice. Pentylenetetrazole effectiveness was dependent on the time of treatment; cognitive performance improved after treatment during the light (inactive) phase, but not during the dark (active) phase. Chronic pentylenetetrazole treatment normalized EEG power spectra in TS mice.
  
  
  CONCLUSIONS
  Low doses of pentylenetetrazole were safe, produced long-lasting cognitive improvements and have the potential of fulfilling an unmet therapeutic need in Down's syndrome.
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305-5020, USA.
authors.forename: D
authors.initials: D
authors.lastname: Colas
authors.forename: B
authors.initials: B
authors.lastname: Chuluun
authors.forename: D
authors.initials: D
authors.lastname: Warrier
authors.forename: M
authors.initials: M
authors.lastname: Blank
authors.forename: D Z
authors.initials: DZ
authors.lastname: Wetmore
authors.forename: P
authors.initials: P
authors.lastname: Buckmaster
authors.forename: C C
authors.initials: CC
authors.lastname: Garner
authors.forename: H C
authors.initials: HC
authors.lastname: Heller
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002940:Circadian Rhythm; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D004569:Electroencephalography; D058787:GABA-A Receptor Antagonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects; D051379:Mice; D010433:Pentylenetetrazole / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D058787:GABA-A Receptor Antagonists; D010433:Pentylenetetrazole