title: Chronic Ampakine Treatments Stimulate Dendritic Growth and Promote Learning in Middle-Aged Rats.
abstract: Positive allosteric modulators of AMPA-type glutamate receptors (ampakines) have been shown to rescue synaptic plasticity and reduce neuropathology in rodent models of cognitive disorders. Here we tested whether chronic ampakine treatment offsets age-related dendritic retraction in middle-aged (MA) rats. Starting at 10 months of age, rats were housed in an enriched environment and given daily treatment with a short half-life ampakine or vehicle for 3 months. Dendritic branching and spine measures were collected from 3D reconstructions of Lucifer yellow-filled CA1 pyramidal cells. There was a substantial loss of secondary branches, relative to enriched 2.5-month-old rats, in apical and basal dendritic fields of vehicle-treated, but not ampakine-treated, 13-month-old rats. Baseline synaptic responses in CA1 were only subtly different between the two MA groups, but long-term potentiation was greater in ampakine-treated rats. Unsupervised learning of a complex environment was used to assess treatment effects on behavior. Vehicle- and drug-treated rats behaved similarly during a first 30 min session in the novel environment but differed markedly on subsequent measures of long-term memory. Markov sequence analysis uncovered a clear increase in the predictability of serial movements between behavioral sessions 2 and 3 in the ampakine, but not vehicle, group. These results show that a surprising degree of dendritic retraction occurs by middle age and that this can be mostly offset by pharmacological treatments without evidence for unwanted side effects. The functional consequences of rescue were prominent with regard to memory but also extended to self-organization of behavior.
  
  
  CONCLUSIONS
  Brain aging is characterized by a progressive loss of dendritic arbors and the emergence of impairments to learning-related synaptic plasticity. The present studies show that dendritic losses are evident by middle age despite housing in an enriched environment and can be mostly reversed by long-term, oral administration of a positive allosteric modulator of AMPA-type glutamate receptors. Dendritic recovery was accompanied by improvements to both synaptic plasticity and the encoding of long-term memory of a novel, complex environment. Because the short half-life compound had no evident negative effects, the results suggest a plausible strategy for treating age-related neuronal deterioration.
authors: Department of Anatomy and Neurobiology.
authors: Julie C
authors: JC
authors: Lauterborn
authors: Department of Anatomy and Neurobiology.
authors: Linda C
authors: http://orcid.org/0000-0002-9921-3502
authors: LC
authors: Palmer
authors: Department of Anatomy and Neurobiology.
authors: Yousheng
authors: Y
authors: Jia
authors: Department of Anatomy and Neurobiology.
authors: Danielle T
authors: DT
authors: Pham
authors: Department of Anatomy and Neurobiology.
authors: Bowen
authors: B
authors: Hou
authors: Department of Anatomy and Neurobiology.
authors: Weisheng
authors: W
authors: Wang
authors: Department of Anatomy and Neurobiology.
authors: Brian H
authors: BH
authors: Trieu
authors: Department of Anatomy and Neurobiology.
authors: Conor D
authors: CD
authors: Cox
authors: Department of Anatomy and Neurobiology.
authors: Svetlana
authors: http://orcid.org/0000-0002-3650-8186
authors: S
authors: Kantorovich
authors: Department of Anatomy and Neurobiology, Department of Neurobiology and Behavior, and ga.s.lynch@gmail.com cmariegall@gmail.com.
authors: Christine M
authors: CM
authors: Gall
authors: Department of Anatomy and Neurobiology, Department of Psychiatry and Human Behavior, University of California, Irvine, California 92697 ga.s.lynch@gmail.com cmariegall@gmail.com.
authors: Gary
authors: G
authors: Lynch
mesh_terms: D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D003712:Dendrites / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000008:administration & dosage* / Q000502:physiology
chemical_list: D018091:Receptors, AMPA
keywords: CA1; Markov analysis; enriched environment; hippocampus; long-term potentiation; spine