title: Enhancing GABA Signaling during Middle Adulthood Prevents Age-Dependent GABAergic Interneuron Decline and Learning and Memory Deficits in ApoE4 Mice.
abstract: Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). However, the underlying mechanisms are still poorly understood. We previously reported that female apoE4 knock-in (KI) mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined by Morris water maze (MWM), in aged mice. Enhancing GABA signaling by treating aged apoE4-KI mice with the GABAA receptor potentiator pentobarbital (PB) for 4 weeks before and during MWM rescued the learning and memory deficits. Here, we report that withdrawal of PB treatment for 2 weeks before MWM abolished the rescue in aged apoE4-KI mice, suggesting the importance of continuously enhancing GABA signaling in the rescue. However, treating apoE4-KI mice during middle adulthood (9-11 months of age) with PB for 6 weeks prevented age-dependent hilar GABAergic interneuron decline and learning and memory deficits, when examined at 16 month of age. These data imply that increasing inhibitory tone after substantial GABAergic interneuron loss may be an effective symptomatic, but not a disease-modifying, treatment for AD related to apoE4, whereas a similar intervention before substantial interneuron loss could be a disease-modifying therapeutic.
  
  
  CONCLUSIONS
  We previously reported that female apoE4-KI mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of cognitive deficits in aged mice. The current study demonstrates that enhancing GABA signaling by treating aged apoE4-KI mice with a GABAA receptor potentiator pentobarbital (PB) before and during behavioral tests rescued the cognitive deficits; but withdrawal of PB treatment for 2 weeks before the tests abolished the rescue, suggesting the importance of continuously enhancing GABA signaling. However, treating apoE4-KI mice during middle adulthood with PB for a short period of time prevented age-dependent hilar GABAergic interneuron decline and cognitive deficits late in life, suggesting early intervention by enhancing GABA signaling as a potential strategy to prevent AD related to apoE4.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, and Biomedical Sciences Graduate Program, and.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Tong
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, and.
authors.forename: Seo Yeon
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, and.
authors.forename: Yaisa
authors.initials: Y
authors.lastname: Andrews-Zwilling
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, and.
authors.forename: Alyssa
authors.identifier: http://orcid.org/0000-0001-6673-6086
authors.initials: A
authors.lastname: Yang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, and.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lin
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, and.
authors.forename: Hanci
authors.initials: H
authors.lastname: Lei
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, and Biomedical Sciences Graduate Program, and Departments of Neurology and Pathology, University of California, San Francisco, California 94143 yadong.huang@gladstone.ucsf.edu.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000375:Aging / Q000235:genetics / Q000523:psychology; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics*; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology*; D055879:Gene Knock-In Techniques; D007395:Interneurons / Q000187:drug effects*; D007859:Learning Disabilities / Q000235:genetics / Q000517:prevention & control*; D018782:Maze Learning; D008569:Memory Disorders / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D010424:Pentobarbital / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; D018755:GABA Agonists; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D010424:Pentobarbital
keywords: Alzheimer's disease; apoE; inhibitory neuron; learning and memory; middle adulthood; pentobarbital