Age-dependent enhancement of hippocampal long-term potentiation and impairment of spatial learning through the Rho-associated kinase pathway in protein tyrosine phosphatase receptor type Z-deficient mice.
Although protein tyrosine phosphatases (PTPs) are expressed abundantly in the brain, their roles in synaptic plasticity have not been well elucidated. In this study, we have examined the physiological functions of Ptprz, which is a receptor-type PTP expressed predominantly in the brain as a chondroitin sulfate proteoglycan. We have examined phenotypes of mutant mice deficient in Ptprz using electrophysiological, pharmacological, and behavioral approaches. Mutant mice exhibit enhanced long-term potentiation (LTP) in the CA1 region of hippocampal slices and impaired spatial learning abilities in an age-dependent manner: young adult (<10 weeks old) mutant mice show normal LTP and learning abilities in the Morris water maze task, whereas adult (>13 weeks old) mutant mice exhibit enhanced LTP and impairment in the task. The enhanced LTP is specifically canceled out by pharmacological inhibition of Rho-associated kinase (ROCK), a major downstream effector of Rho. These findings suggest that the lack of Ptprz leads to aberrant activation of ROCK and resultantly to enhanced LTP in the slice and learning impairments in the animal.
Niisato
Kazue
K
Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Fujikawa
Akihiro
A
Komai
Shoji
S
Shintani
Takafumi
T
Watanabe
Eiji
E
Sakaguchi
Gaku
G
Katsuura
Goro
G
Manabe
Toshiya
T
Noda
Masaharu
M
D000375:Aging / Q000378:metabolism / Q000523:psychology*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D011508:Chondroitin Sulfate Proteoglycans; D004789:Enzyme Activation / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000201:enzymology* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008569:Memory Disorders / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases
D000577:Amides; D011508:Chondroitin Sulfate Proteoglycans; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011725:Pyridines; D011956:Receptors, Cell Surface; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D017027:Protein Tyrosine Phosphatases; C516896:Ptprz1 protein, mouse; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5