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

Abstract

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 (Ͻ10 weeks old) mutant mice show normal LTP and learning abilities in the Morris water maze task, whereas adult (Ͼ13 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.

Extracellular matrix of the central nervous system: from neglect to challenge

“…This functional property appears to be mostly core protein-dependent in versican V0, V1 and V2 (Dutt, Stöckli and Zimmermann unpublished;Niederöst et al 1999;Schmalfeldt et al 2000;), neurocan and phosphacan (Maeda and Noda 1996), whereas no inhibition of brevican (Yamada et al 1997a) and cartilage-derived aggrecan (Snow et al 1990) has been detected after chondroitinase ABC digestion. Notably, we also observed two-to threefold reductions, but never an abolition of the inhibitory capacity of versican V2 in stripe choice experiments after complete glycosaminoglycan-removal (Schmalfeldt et al Table 2 Available ECM-knockout mouse strains LTP Hippocampal long-term potentiation, EAE experimental autoimmune encephalomyelitis, PNN perineuronal net, ND not described Brevican (Brakebusch et al 2002); neurocan (Zhou et al 2001); versican (Mjaatvedt et al 1998); aggrecan ; RPTP-/phosphacan (Harroch et al 2000(Harroch et al , 2002Niisato et al 2005); TnR (Bruckner et al 2000;Freitag et al 2003;Haunso et al 2000;Montag-Sallaz and Montag 2003;Saghatelyan et al 2004;Weber et al 1999); TnC (Evers et al 2002;Forsberg et al 1996;Fukamauchi et al 1996;Kiernan et al 1999;Saga et al 1992); HAPLN1/Crtl1 (Watanabe and Yamada 1999); HAS2 (Camenisch et al 2000); HAS3 (Bai et al 2005) . This moderate decrease might be related to the partial collapse of the extended core protein structure after elimination of the highly negatively charged chondroitin sulfate side chains.…”

Neurons and Glia Modify Receptor Protein-tyrosine Phosphatase ζ (RPTPζ)/Phosphacan with Cell-specific O-Mannosyl Glycans in the Developing Brain

“…RPTP/phosphacan is required for normal nervous system development and function (32,33,35). Whether O-mannosylation of this protein contributes to its function has been more difficult to determine, due to the predominating role of another highly mannosylated glycoprotein (␣-DG) in CMDs.…”

“…Recent work detailed the structures of glycans carrying the HNK-1 epitope on RPTP/phosphacan and showed that this protein is the main carrier of unique O-mannose-linked terminal HNK-1 glycans (62). HNK-1 glycans have a role in learning and memory (63,64), and RPTP/phosphacan knock-out mice have been shown to exhibit parallel deficits (35), suggesting that O-mannosyl glycans may be responsible for these changes.…”

Involvement of the cerebellum in cocaine-induced memory

“…One of the first and most influential studies which evaluated the role of PNNs in the experience-dependent plasticity is the one conducted by Pizzorusso and colleagues performance (Niisato et al, 2005). Moreover, it has been found that genetic deletion of link proteins also enhances plasticity mechanisms underlying ocular dominance .…”

“…performance (Niisato et al, 2005). Moreover, it has been found that genetic deletion of link proteins also enhances plasticity mechanisms underlying ocular dominance .…”