title: Impairment of select forms of spatial memory and neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4.
abstract: Aquaporin-4 (AQP4) is the major water channel in the CNS and is primarily expressed in astrocytes. Little is known about the potential for AQP4 to influence synaptic plasticity, although many studies have shown that it regulates the response of the CNS to injury. Therefore, we evaluated long-term potentiation (LTP) and long-term depression (LTD) in AQP4 knock-out (KO) and wild-type mice. KO mice exhibited a selective defect in LTP and LTD without a change in basal transmission or short-term plasticity. Interestingly, the impairment in LTP in KO mice was specific for the type of LTP that depends on the neurotrophin BDNF, which is induced by stimulation at theta rhythm [theta-burst stimulation (TBS)-LTP], but there was no impairment in a form of LTP that is BDNF independent, induced by high-frequency stimulation. LTD was also impaired in KO mice, which was rescued by a scavenger of BDNF or blockade of Trk receptors. TrkB receptors, which mediate effects of BDNF on TBS-LTP, were not altered in KO mice, but p75NTR, the receptor that binds all neurotrophins and has been implicated in some types of LTD, was decreased. The KO mice also exhibited a cognitive defect, which suggests a new role for AQP4 and astrocytes in normal cognitive function. This defect was evident using a test for location-specific object memory but not Morris water maze or contextual fear conditioning. The results suggest that AQP4 channels in astrocytes play an unanticipated role in neurotrophin-dependent plasticity and influence behavior.
authors.affiliation: The Nathan Kline Institute for Psychiatric Research, Center for Dementia Research, Orangeburg, New York 10962, USA.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Skucas
authors.forename: Ian B
authors.initials: IB
authors.lastname: Mathews
authors.forename: Jianmin
authors.initials: J
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Cheng
authors.forename: Andrew
authors.initials: A
authors.lastname: Treister
authors.forename: Aine M
authors.initials: AM
authors.lastname: Duffy
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Wood
authors.forename: Devin K
authors.initials: DK
authors.lastname: Binder
authors.forename: Helen E
authors.initials: HE
authors.lastname: Scharfman
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency*; D001703:Biophysics / Q000379:methods; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D016009:Chi-Square Distribution; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D026121:Indole Alkaloids / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D051401:Aquaporin 4; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; C049985:staurosporine aglycone; D020813:Receptor, trkB