The Effect of an NCAM Mimetic on Learning and Memory Impairment in an Animal Model of Schizophrenia

Thomas Secher

The Effect of an NCAM Mimetic on Learning and Memory Impairment in an Animal Model of Schizophrenia

Thomas Secher

Eyepath Lab

Abstract

FGL er et lille peptid, der er afledt af det neurale celle adhæsions molekyle. Det er blevet vist at
FGL kan binde og aktiverer fibroblast vækstfaktor receptoren. Det er blevet demonstreret i in
vitro og in vivo studier at FGL kan inducerer neuritudvækst, neuronal overlevelse og synaptisk
plasticitet. Endvidere kan FGL øge hukommelse hos normale dyr.
Skizofreni er en heterogen psykiatrisk sygdom, hvor forstyrrelser i informationsbearbejdning
og højere kognitive funktioner menes at være fundamentale elementer. De kognitive
forstyrrelser er af større betydning for patienternes mulighed for revalidering og mulighed for
at fungere i dagligdagen, men påvirkes kun i begrænset omfang af de kendte antipsykotika.
Det overordnede mål med det nærværende projekt har været at undersøge om FGL kunne have
en gavnlig effekt på indlærings- og hukommelsesforstyrrelser i en rottemodel for skizofreni.
Neonatal behandling med N-metyl-D-aspartat (NMDA) receptor antagonisten phencyclidin
(PCP) på postnatal dag 7, 9 og 11 forårsager akut neurodegeneration og langtidsvarende
forstyrrelser i indlæring og hukommelse og andre adfærdsmæssige ændringer med relevans for
skizofreni. For at undersøge en mulig effekt af FGL i denne model blev voksne PCP rotter
testede for rummelig referencehukommelse, reversal og arbejdshukommelse forstyrrelser i
Morris’ water maze. Rotterne i disse test blev samtidig underkastet forskellige FGL
behandlingsregimer. To PCP doser (10 og 30 mg/kg) blev testet. Adfærdsundersøgelserne blev
suppleret med immunohistokemiske undersøgelser af neurodegeneration og NMDA receptor
aktivering i relevante hjerneområder.
Resultaterne viste at neonatal PCP behandling forårsagede langtidsvarende forstyrrelser i
rummelig indlæring og hukommelse. Den høje PCP dosis resulterede i mere robuste
forstyrrelser i alle tre water maze test, hvorimod den lave dosis kun forårsagede forstyrrelser i
reversaltesten. FGL behandlingen var ikke i stand til reverser forstyrrelserne i reversaltesten
induceret af den lave PCP dosis. Imidlertid havde FGL nogen normaliserende effekt på
arbejdshukommelsesforstyrrelserne forårsaget af den høje PCP dosis. De immunohistokemiske
undersøgelser antydede at FGL behandlingen var i stand til at reducere apoptotisk celledød i
det frontale kortex i rotteunger og til at forøge NMDA receptor aktivering i hippocampus i
voksne rotter.
Det nærværende projekt understøtter at neonatal PCP behandling forårsager langtidsvarende
forstyrrelser i rummelig indlæring og hukommelse. Effekten af FGL på disse forstyrrelser var
generelt meget lille. FGL havde dog nogen normaliserende effekt i arbejdshukommelsestesten.
Den svage effekt af FGL i denne dyremodel begrænser udsigten til at bruge dette peptid som
mulig behandlingsstrategi for kognitive forstyrrelser i skizofreni. FGL var også i stand til at
forøge aktiveringen af NMDA receptorer i hippocampus, hvilket muligvis afspejler en
molekylær mekanisme for FGL til at påvirke hukommelsesprocessor.

Originalsprog	Engelsk

Antal sider	172
Status	Udgivet - 2009

Citationsformater

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title = "The Effect of an NCAM Mimetic on Learning and Memory Impairment in an Animal Model of Schizophrenia",

abstract = "FGL is a small synthetic peptide that is derived from the neural cell adhesion molecule. It hasbeen demonstrated that FGL can bind and activate the fibroblast growth factor receptor. Invitro and in vivo studies have shown that FGL can promote such processes as neuriteoutgrowth, neuronal survival, and synaptic plasticity. Furthermore, it can act as a memoryenhancer in normal animals.Schizophrenia is a heterogeneous psychiatric disorder. Disturbances in information processingand higher cognitive function including deficits in working memory are believed represent acore feature of schizophrenia. The cognitive dysfunction is strongly related to the functionaloutcome of patients, but is only minimally affected by existing antipsychotic treatment.The general aim on the present project was to investigate if FGL could have a beneficial effecton learning and memory deficits in a rat model for schizophrenia.Neonatal treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine(PCP) on postnatal days 7, 9, and 11 has been shown to induce acute neurodegeneration andlong-term cognitive deficits and other behavioral abnormalities relevant to schizophrenia. Toevaluate the effect of FGL in this model, adult PCP rats were tested for spatial referencememory, reversal learning, and working memory deficits in Morris{\textquoteright} water maze in combinationwith different FGL treatment regimens. Two doses of PCP (10 and 30 mg/kg) were tested.Behavioral testing was complemented by immunohistochemical investigation ofneurodegeneration and NMDA receptor activation in relevant brain regions.The results show that neonatal PCP treatment induces long-term impairment in spatiallearning and memory. The higher PCP dose produced more robust deficits in all three tasks ofthe water maze, whereas the lower dose only resulted in reversal learning impairment. FGLtreatment was not able to reverse the impairment in reversal learning caused by the lower PCPdose. However, FGL treatment had some normalizing effect on the working memory deficitscaused by the higher PCP dose. The immunohistochemical results indicated that FGLtreatment was able to reduce apoptotic cell death in the frontal cortex in pups and to increaseNMDA receptor activation in the hippocampus in adultsIn the present project, further evidence was obtained that neonatal PCP treatment induceslong-term impairment in spatial learning and memory. The effect of FGL on these deficits was,in general, very small; however, the peptide had some normalizing effect in the workingmemory task. The weak effects of FGL in this animal model limit the prospect of this peptide asa possible treatment for the cognitive impairment seen in schizophrenia. FGL was also able toincrease NMDA receptor activation in the hippocampus, which might reflect a possiblemolecular mechanism for this peptide to enhance memory.",

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N2 - FGL is a small synthetic peptide that is derived from the neural cell adhesion molecule. It hasbeen demonstrated that FGL can bind and activate the fibroblast growth factor receptor. Invitro and in vivo studies have shown that FGL can promote such processes as neuriteoutgrowth, neuronal survival, and synaptic plasticity. Furthermore, it can act as a memoryenhancer in normal animals.Schizophrenia is a heterogeneous psychiatric disorder. Disturbances in information processingand higher cognitive function including deficits in working memory are believed represent acore feature of schizophrenia. The cognitive dysfunction is strongly related to the functionaloutcome of patients, but is only minimally affected by existing antipsychotic treatment.The general aim on the present project was to investigate if FGL could have a beneficial effecton learning and memory deficits in a rat model for schizophrenia.Neonatal treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine(PCP) on postnatal days 7, 9, and 11 has been shown to induce acute neurodegeneration andlong-term cognitive deficits and other behavioral abnormalities relevant to schizophrenia. Toevaluate the effect of FGL in this model, adult PCP rats were tested for spatial referencememory, reversal learning, and working memory deficits in Morris’ water maze in combinationwith different FGL treatment regimens. Two doses of PCP (10 and 30 mg/kg) were tested.Behavioral testing was complemented by immunohistochemical investigation ofneurodegeneration and NMDA receptor activation in relevant brain regions.The results show that neonatal PCP treatment induces long-term impairment in spatiallearning and memory. The higher PCP dose produced more robust deficits in all three tasks ofthe water maze, whereas the lower dose only resulted in reversal learning impairment. FGLtreatment was not able to reverse the impairment in reversal learning caused by the lower PCPdose. However, FGL treatment had some normalizing effect on the working memory deficitscaused by the higher PCP dose. The immunohistochemical results indicated that FGLtreatment was able to reduce apoptotic cell death in the frontal cortex in pups and to increaseNMDA receptor activation in the hippocampus in adultsIn the present project, further evidence was obtained that neonatal PCP treatment induceslong-term impairment in spatial learning and memory. The effect of FGL on these deficits was,in general, very small; however, the peptide had some normalizing effect in the workingmemory task. The weak effects of FGL in this animal model limit the prospect of this peptide asa possible treatment for the cognitive impairment seen in schizophrenia. FGL was also able toincrease NMDA receptor activation in the hippocampus, which might reflect a possiblemolecular mechanism for this peptide to enhance memory.

AB - FGL is a small synthetic peptide that is derived from the neural cell adhesion molecule. It hasbeen demonstrated that FGL can bind and activate the fibroblast growth factor receptor. Invitro and in vivo studies have shown that FGL can promote such processes as neuriteoutgrowth, neuronal survival, and synaptic plasticity. Furthermore, it can act as a memoryenhancer in normal animals.Schizophrenia is a heterogeneous psychiatric disorder. Disturbances in information processingand higher cognitive function including deficits in working memory are believed represent acore feature of schizophrenia. The cognitive dysfunction is strongly related to the functionaloutcome of patients, but is only minimally affected by existing antipsychotic treatment.The general aim on the present project was to investigate if FGL could have a beneficial effecton learning and memory deficits in a rat model for schizophrenia.Neonatal treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine(PCP) on postnatal days 7, 9, and 11 has been shown to induce acute neurodegeneration andlong-term cognitive deficits and other behavioral abnormalities relevant to schizophrenia. Toevaluate the effect of FGL in this model, adult PCP rats were tested for spatial referencememory, reversal learning, and working memory deficits in Morris’ water maze in combinationwith different FGL treatment regimens. Two doses of PCP (10 and 30 mg/kg) were tested.Behavioral testing was complemented by immunohistochemical investigation ofneurodegeneration and NMDA receptor activation in relevant brain regions.The results show that neonatal PCP treatment induces long-term impairment in spatiallearning and memory. The higher PCP dose produced more robust deficits in all three tasks ofthe water maze, whereas the lower dose only resulted in reversal learning impairment. FGLtreatment was not able to reverse the impairment in reversal learning caused by the lower PCPdose. However, FGL treatment had some normalizing effect on the working memory deficitscaused by the higher PCP dose. The immunohistochemical results indicated that FGLtreatment was able to reduce apoptotic cell death in the frontal cortex in pups and to increaseNMDA receptor activation in the hippocampus in adultsIn the present project, further evidence was obtained that neonatal PCP treatment induceslong-term impairment in spatial learning and memory. The effect of FGL on these deficits was,in general, very small; however, the peptide had some normalizing effect in the workingmemory task. The weak effects of FGL in this animal model limit the prospect of this peptide asa possible treatment for the cognitive impairment seen in schizophrenia. FGL was also able toincrease NMDA receptor activation in the hippocampus, which might reflect a possiblemolecular mechanism for this peptide to enhance memory.

M3 - Ph.D. thesis

BT - The Effect of an NCAM Mimetic on Learning and Memory Impairment in an Animal Model of Schizophrenia

ER -

The Effect of an NCAM Mimetic on Learning and Memory Impairment in an Animal Model of Schizophrenia

Abstract

Fingeraftryk

Citationsformater