title: Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments.
abstract: BACKGROUND
  Tau is a microtubule stabilizing protein and is mainly expressed in neurons. Tau aggregation into oligomers and tangles is considered an important pathological event in tauopathies, such as frontotemporal dementia (FTD) and Alzheimer's disease (AD). Tauopathies are also associated with deficits in synaptic plasticity such as long-term potentiation (LTP), but the specific role of tau in the manifestation of these deficiencies is not well-understood. We examined long lasting forms of synaptic plasticity in JNPL3 (BL6) mice expressing mutant tau that is identified in some inherited FTDs.
  
  
  RESULTS
  We found that aged (>12 months) JNPL3 (BL6) mice exhibit enhanced hippocampal late-phase (L-LTP), while young JNPL3 (BL6) mice (age 6 months) displayed normal L-LTP. This enhanced L-LTP in aged JNPL3 (BL6) mice was rescued with the GABAAR agonist, zolpidem, suggesting a loss of GABAergic function. Indeed, we found that mutant mice displayed a reduction in hippocampal GABAergic interneurons. Finally, we also found that expression of mutant tau led to severe sensorimotor-gating and hippocampus-dependent memory deficits in the aged JNPL3 (BL6) mice.
  
  
  CONCLUSIONS
  We show for the first time that hippocampal GABAergic function is impaired by pathological tau protein, leading to altered synaptic plasticity and severe memory deficits. Increased understanding of the molecular mechanisms underlying the synaptic failure in AD and FTD is critical to identifying targets for therapies to restore cognitive deficiencies associated with tauopathies.
authors.affiliation: Department of Physiology & Neuroscience, New York University School of Medicine, 550 First Ave, SRB 610, New York, NY 10016, USA. Charles.Hoeffer@nyumc.org.
authors.forename: Josien
authors.initials: J
authors.lastname: Levenga
authors.forename: Pavan
authors.initials: P
authors.lastname: Krishnamurthy
authors.forename: Hameetha
authors.initials: H
authors.lastname: Rajamohamedsait
authors.forename: Helen
authors.initials: H
authors.lastname: Wong
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Franke
authors.forename: Peter
authors.initials: P
authors.lastname: Cain
authors.forename: Einar M
authors.initials: EM
authors.lastname: Sigurdsson
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hoeffer
mesh_terms: D000818:Animals; D002452:Cell Count; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007395:Interneurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011725:Pyridines / Q000494:pharmacology; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology*; D024801:Tauopathies / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D000077334:Zolpidem; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D058785:GABA-A Receptor Agonists; C054369:MAPT protein, human; D011725:Pyridines; D016875:tau Proteins; D000077334:Zolpidem