title: Early deficits in declarative and procedural memory dependent behavioral function in a transgenic rat model of Huntington's disease.
abstract: In Huntington's disease (HD) cognitive deficits co-exist with motor impairments, both contributing to the overall disease symptomology. Despite short-term and working memory impairments, learning and other non-motoric behavioral deficits arising from the damage to frontostriatal loop being common in HD patients, most of the experimental work with transgenic animals focuses on motor symptoms. The transgenic rat model (tgHD) recapitulates many hallmark HD-like symptoms, such as huntingtin aggregates, cellular loss and dysfunction, and motor, and some cognitive deficits. In the current study we tested tgHD rats in two different cognitive, water maze competition paradigms to learn more about the impact of the transgene on learning and memory processing using hippocampal- and striatal-based memory systems. The tgHD rats had early and robust cognitive deficits in learning and memory function in both paradigms. Specifically, the transgenic animals were impaired in task acquisition and committed more procedural errors with the strongest phenotype amongst the homozygote tgHD. Although the transgenic animals were capable of using both procedural and declarative memory, their response patterns were distinct from wild-type animals. Wide spread huntingtin aggregates were observed at 13 months, but neither PET nor autoradiography indicated neuronal loss or dysfunction in striatal dopamine receptor population. In summary, the homozygote tgHD showed a robust learning and memory impairment prior to any clear motor deficits, or striatal dysfunction. However, the data were not conclusive regarding how the memory systems were compromised and the precise nature and underlying mechanism of the cognitive deficit in the tgHD model requires further investigation.
authors.affiliation: Laboratory for Molecular Neurosurgery, Stereotactic and Functional Neurosurgery, University Hospital Freiburg, Engesserstrasse 4,Freiburg, Germany. robert.kirch@uniklinik-freiburg.de
authors.forename: Robert D
authors.initials: RD
authors.lastname: Kirch
authors.forename: Philipp T
authors.initials: PT
authors.lastname: Meyer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Geisler
authors.forename: Friederike
authors.initials: F
authors.lastname: Braun
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gehrig
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Langen
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
authors.forename: Guido
authors.initials: G
authors.lastname: Nikkhah
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Cassel
authors.forename: Máté D
authors.initials: MD
authors.lastname: Döbrössy
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005462:Fluorine Radioisotopes; D059907:Functional Neuroimaging / Q000379:methods / Q000523:psychology*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000523:psychology*; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000523:psychology*; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D049268:Positron-Emission Tomography / Q000379:methods / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012457:Salicylamides
chemical_list: D001786:Blood Glucose; D005462:Fluorine Radioisotopes; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C100958:desmethoxyfallypride