Mice lacking leukocyte common antigen-related (LAR) protein tyrosine phosphatase domains demonstrate spatial learning impairment in the two-trial water maze and hyperactivity in multiple behavioural tests

Kolkman, M.J.; Streijger, Femke; Linkels, Marianne; Bloemen, Marjon; Heeren, D. J.; Hendriks, Wiljan; Zee, Catharina E.E.M. Van der

doi:10.1016/j.bbr.2004.02.006

Cited by 40 publications

(31 citation statements)

References 57 publications

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“…It is unlikely that this behavioral defect simply reflects the extraordinarily high level of hyperactivity, because BAC TG mice often exhibit normal motor activity in their home cage and are capable of eating food pellets from the cage ceiling (data not shown). Moreover, hyperactivity per se does not necessarily cause less nest-building activity in mice (50). It is also unlikely that hyperactivity increased body temperature in TG mice, which indirectly reduced the size of nests, because WT and TG mice have indistinguishable levels of body temperature [WT, 37.2°C (SEM Ϯ 0.26); TG, 37.1°C (SEM Ϯ 0.31); t(14) ϭ 0.31, not significant (n.s.…”

Section: Resultsmentioning

confidence: 99%

A 200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice

Hiroi

Zhu

Lee

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Human chromosome 22q11.2 has been implicated in various behavioral abnormalities, including schizophrenia and other neuropsychiatric͞behavioral disorders. However, the specific genes within 22q11.2 that contribute to these disorders are still poorly understood. Here, we show that an Ϸ200-kb segment of human 22q11.2 causes specific behavioral abnormalities in mice. Mice that overexpress an Ϸ200-kb region of human 22q11.2, containing CDCrel, GP1B␤, TBX1, and WDR14, exhibited spontaneous sensitization of hyperactivity and a lack of habituation. These effects were ameliorated by antipsychotic drugs. The transgenic mice were also impaired in nesting behavior. Although Tbx1 has been shown to be responsible for many physical defects associated with 22q11.2 haploinsufficiency, Tbx1 heterozygous mice did not display these behavioral abnormalities. Our results show that the Ϸ200-kb region of 22q11.2 contains a gene(s) responsible for behavioral abnormalities and suggest that distinct genetic components within 22q11.2 mediate physical and behavioral abnormalities.22q11 ͉ habituation ͉ hyperactivity ͉ mouse model ͉ schizophrenia T he genetic abnormality in 22q11.2 is better delineated than those of most human chromosomal loci that have been implicated in neuropsychiatric and behavioral disorders. Higherthan-expected rates of schizophrenia and other neuropsychiatric disorders are seen in adult patients with 1.5-to 3-Mb haploinsufficiency (i.e., deletion) in 22q11.2 (1-7). Reciprocal duplication of the same chromosomal region also has been identified, and these individuals exhibit impulsivity, aggression, oppositional defiant disorder, social immaturity, short attention spans, attention deficit disorder, and cognitive deficits (8)(9)(10)(11)(12). Because most of these individuals are infants or children at present, their neuropsychiatric disorders have not been fully characterized. However, preliminary data show that individuals with duplications also suffer from neuropsychiatric disorders (9, 12).It remains poorly understood precisely how a gene or set of genes within 22q11.2 contributes to these behavioral phenotypes. In non-duplication͞deletion cases, polymorphisms of various genes residing in 22q11.2 have been associated with schizophrenia and related behavioral and cognitive defects (13,14). For example, a high activity allele of catechol-O-methyl-transferase (COMT) is associated with a heightened risk for schizophrenia in humans (15). As for 22q11.2 deletion cases, haploinsufficiency is associated with prepulse inhibition (PPI) deficits in humans (16), and a comparable deficit is seen in mice with a relatively large 1-Mb heterozygosity, including 19 genes of the mouse synteny of human 22q11.2 (17). Mice defective for either Prodh (proline dehydrogenase) or Zdhhc8 (zinc finger, DHHC-type containing 8) exhibit much weaker PPI deficits (18,19). Given the presumed polygenetic nature of neuropsychiatric disorders and the weak PPI deficits observed in Prodh-and Zdhhc8-deficient mice, it is likely that other 22q11.2 genes cont...

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Section: Resultsmentioning

confidence: 99%

A 200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice

Hiroi

Zhu

Lee

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…These mutant mice display decreased size and number of basal forebrain cholinergic neurons and deficient innervation of the hippocampal dentate gyrus (43,44), show deficiencies in regenerative neurite outgrowth (45,46), and develop spatial learning impairment and hyperactivity (47). LAR interacts with liprins, which regulate glutamate receptor clustering in dendritic spines and differentiation of presynaptic termini in neurons (48 -52).…”

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confidence: 99%

Presenilin/γ-Secretase-mediated Cleavage Regulates Association of Leukocyte-Common Antigen-related (LAR) Receptor Tyrosine Phosphatase with β-Catenin

Haapasalo

Kim

Carey

et al. 2007

Journal of Biological Chemistry

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Leukocyte-common antigen-related (LAR) receptor tyrosine phosphatase regulates cell adhesion and formation of functional synapses and neuronal networks. Here we report that LAR is sequentially cleaved by ␣-and presenilin (PS)/␥-secretases, which also affect signaling and/or degradation of type-I membrane proteins including the Alzheimer disease-related ␤-amyloid precursor protein. Similar to the previously characterized PS/␥-secretase substrates, inhibition of ␥-secretase activity resulted in elevated LAR C-terminal fragment (LAR-CTF) levels in stably LAR-overexpressing Chinese hamster ovary (CHO) cells, human neuroglioma cells, and mouse cortical neurons endogenously expressing LAR. Furthermore, LAR-CTF levels increased in cells lacking functional PS, indicating that ␥-secretase-mediated cleavage of LAR was PS-dependent. Inhibition of ␣-secretase activity by TAPI-1 treatment blocked LAR-CTF accumulation, demonstrating that prior ectodomain shedding was prerequisite for PS/␥-secretase-mediated cleavage of LAR. Moreover, we identified the product of PS/␥-secretase cleavage, LAR intracellular domain (LICD), both in vitro and in cells overexpressing full-length (FL) LAR or LAR-CTFs. LAR localizes to cadherin-␤-catenin-based cellular junctions. Assembly and disassembly of these junctions are regulated by tyrosine phosphorylation. We found that endogenous tyrosine-phosphorylated ␤-catenin coimmunoprecipitated with LAR in CHO cells. However, when PS/␥-secretase activity was inhibited, the association between LAR and ␤-catenin significantly diminished. In addition to cell adhesion, ␤-catenin is involved in transcriptional regulation. We observed that LICD significantly decreased transcription of cyclin D1, one of the ␤-catenin target genes. Thus, our results show that PS/␥-secretase-mediated cleavage of LAR controls LAR-␤-catenin interaction, suggesting an essential role for PS/␥-secretase in the regulation of LAR signaling. Presenilin (PS)2 /␥-secretase is a high molecular weight enzymatic complex composed of PS1 or PS2, nicastrin, Aph-1, and Pen-2 (1-5). PS/␥-secretase plays a key role in the pathogenesis of Alzheimer disease (AD) by cleaving ␤-amyloid precursor protein (APP) by regulated intramembraneous processing (RIP) at two adjacent sites (6 -8). Following ectodomain shedding of APP, the ␥-cleavage generates the A␤-peptide, the major constituent of amyloid plaques in AD brain, and a small p3 fragment. The product of the ⑀-cleavage is the APP intracellular domain (AICD) (9 -11). APP ectodomain shedding is mediated by either ␣-secretases of the ADAM family metalloproteases (12, 13) or BACE (␤-site APP cleaving enzyme) (14 -17), producing membrane-bound APP C-terminal fragments (CTFs). In addition to APP, other type-I membrane proteins are known to undergo PS/␥-secretase-mediated RIP (18). Among these are Notch (8), cadherins (19), nectin-1␣ (20), and voltagegated sodium channel ␤2-subunit (21, 22). Similar to APP, these proteins undergo ectodomain shedding prior to ␥-secretase-mediated cleavage and release intrace...

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“…Primarily, this is a novel report in invertebrates that a receptor-like tyrosine phosphatase is involved in memory formation. In vertebrates, there are a number of reports that suggest an involvement of receptorlike tyrosine phosphatases in learning and memory, although it remains to be determined whether such effects are specific to long-term memory formation (Uetani et al, 2000;Skelton et al, 2003;Kolkman et al, 2004). In any case, these observations indicate that signaling via receptor-like tyrosine phosphatases may be a conserved biochemical pathway for learning and memory, as for the cAMP pathway.…”

Section: Discussionmentioning

confidence: 99%

“…However, there were few studies on the involvement in memory formation of PTPs. To date, learning has been shown to be defective only for mouse knock-outs of PTP␣, leukocyte common antigen-related, or PTP␦ (Uetani et al, 2000;Skelton et al, 2003;Kolkman et al, 2004). A major limitation of these studies arises from their inability to distinguish an acute (biochemical) impairment of memory formation from a more chronic abnormality in neurodevelopment (Wallace et al, 1999;Uetani et al, 2000;Kolkman et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Receptor-Like Tyrosine Phosphatase PTP10D Is Required for Long-Term Memory inDrosophila

et al. 2007

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Tyrosine phosphorylation mediates multiple signal transduction pathways that play key roles in developmental processes and behavioral plasticity. The level of tyrosine phosphorylation is regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Extensive studies have investigated the roles of tyrosine kinases in memory formation. However, there were few studies on PTPs. To date, learning has been shown to be defective only for mouse knock-outs of PTP␣, leukocyte common antigen-related, or PTP␦. A major limitation of these studies arises from their inability to distinguish an acute (biochemical) impairment of memory formation from a more chronic abnormality in neurodevelopment. From a behavioral screen for defective long-term memory, we found chi mutants to disrupt expression of the PTP10D protein tyrosine phosphatase gene. We show that chi mutants are normal for learning, early memory, and anesthesia-resistant memory, whereas long-term memory specifically is abolished. Significantly, induction of a heat shock-PTP10D ϩ transgene before training fully rescues the memory defect of chi mutants, thereby demonstrating an acute role for PTP10D in behavioral plasticity. We show that PTP10D is widely expressed in the embryonic CNS and in the adult brain. Transgenic expression of upstream activating sequence-PTP10D ϩ in mushroom bodies is sufficient to rescue the memory defect of chi mutants. Our data clearly demonstrate that signaling through PTP10D in mushroom bodies is critical for the formation of long-term memory.

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Mice lacking leukocyte common antigen-related (LAR) protein tyrosine phosphatase domains demonstrate spatial learning impairment in the two-trial water maze and hyperactivity in multiple behavioural tests

Cited by 40 publications

References 57 publications

A 200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice

A 200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice

Presenilin/γ-Secretase-mediated Cleavage Regulates Association of Leukocyte-Common Antigen-related (LAR) Receptor Tyrosine Phosphatase with β-Catenin

Receptor-Like Tyrosine Phosphatase PTP10D Is Required for Long-Term Memory inDrosophila

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