Alzheimer's disease (AD) is one of the most serious human, medical, and socioeconomic burdens. Here we tested the hypothesis that a rat model of AD (Samaritan; Taconic Pharmaceuticals, USA) based on the application of amyloid beta42 (Abeta42) and the pro-oxidative substances ferrous sulfate heptahydrate and L-buthionine-(S, R)-sulfoximine, will exhibit cognitive deficits and disruption of the glutamatergic and cholinergic systems in the brain. Behavioral methods included the Morris water maze (MWM; long-term memory version) and the active allothetic place avoidance (AAPA) task (acquisition and reversal), testing spatial memory and different aspects of hippocampal function. Neurochemical methods included testing of the NR1/NR2A/NR2B subunits of NMDA receptors in the frontal cortex and CHT1 transporters in the hippocampus, in both cases in the right and left hemisphere separately. Our results show that Samaritan rats(™) exhibit marked impairment in both the MWM and active place avoidance tasks, suggesting a deficit of spatial learning and memory. Moreover, Samaritan rats exhibited significant changes in NR2A expression and CHT1 activity compared to controls rats, mimicking the situation in patients with early stage AD. Taken together, our results corroborate the hypothesis that Samaritan rats are a promising model of AD in its early stages.

Department of Neurophysiology of Memory Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Department of Neurophysiology of Memory Institute of Physiology of the Czech Academy of SciencesPrague Czech Republic; National Institute of Mental HealthKlecany Czech Republic

National Institute of Mental Health Klecany Czech Republic

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Anderson M. C., Bunce J. G., Barbas H. (2015). Prefrontal-hippocampal pathways underlying inhibitory control over memory. Neurobiol. Learn. Mem. 10.1016/j.nlm.2015.11.008 [Epub ahead of print]. PubMed DOI PMC

Arendt T., Bigl V., Arendt A., Tennstedt A. (1983). Loss of neurons in the nucleus basalis of Meynert in Alzheimer’s disease, paralysis agitans and Korsakoff’s disease. Acta. Neuropathol. 61, 101–108. PubMed

Bahník Š. (2014). Carousel Maze Manager (Version 0.4.0) Software Available from https://github.com/bahniks/CM_Manager_0_4_0

Ben-David B. M., Tewari A., Shakuf V., Van Lieshout P. H. (2014). Stroop effects in Alzheimer’s disease: selective attention speed of processing, or color-naming? A meta-analysis. J. Alzheimers. Dis. 38, 923–938. 10.3233/jad-131244 PubMed DOI

Bures J., Fenton A. A., Kaminsky Y., Zinyuk L. (1997). Place cells and place navigation. Proc. Natl. Acad. Sci. U S A 94, 343–350. PubMed PMC

Butterfield D. A., Pocernich C. (2003). The glutamatergic system and Alzheimer’s disease. CNS Drugs 17, 641–652. 10.2165/00023210-200317090-00004 PubMed DOI

Cai Z., Ratka A. (2012). Opioid system and Alzheimer’s disease. Neuromolecular Med. 14, 91–111. 10.1007/s12017-012-8180-3 PubMed DOI

Cui Z., Feng R., Jacobs S., Duan Y., Wang H., Cao X., et al. . (2013). Increased NR2A: NR2B ratio compresses long-term depression range and constrains long-term memory. Sci. Rep. 3: 1036. 10.1038/srep01036 PubMed DOI PMC

Cull-Candy S., Brickley S., Farrant M. (2001). NMDA receptor subunits: diversity, development and disease. Curr. Opin. Neurobiol. 11, 327–335. 10.1016/s0959-4388(00)00215-4 PubMed DOI

Czéh B, Stuchlik A., Wesierska M., Cimadevilla J. M., Pokorný J., Seress L., et al. (2001). Effect of neonatal dentate gyrus lesion on allothetic and idiothetic navigation in rats. Neurobiol. Learn Mem. 75, 190–213. PubMed

D’Hooge R., De Deyn P. P. (2001). Applications of the Morris water maze in the study of learning and memory. Brain Res. Brain Res. Rev. 36, 60–90. 10.1016/s0165-0173(01)00067-4 PubMed DOI

Do Carmo S., Cuello A. C. (2013). Modeling Alzheimer’s disease in transgenic rats. Mol. Neurodegener. 8: 37. 10.1186/1750-1326-8-37 PubMed DOI PMC

Erreger K., Dravid S. M., Banke T. G., Wyllie D. J. A., Treynelis S. F. (2005). Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signaling profiles. J. Physiol. 563, 345–358. 10.3410/f.1023899.284783 PubMed DOI PMC

Fenton A. A., Wesierska M., Kaminsky Y., Bures J. (1998). Both here and there: simultaneous expression of autonomous spatial memories in rats. Proc. Natl. Acad. Sci. U S A 95, 11493–11498. 10.1073/pnas.95.19.11493 PubMed DOI PMC

Gibbs R. B. (2000). Effects of gonadal hormone replacement on measures of basal forebrain cholinergic function. Neuroscience101931–938. 10.1016/s0306-4522(00)00433-4 PubMed DOI

Hatalova H., Radostova D., Pistikova A., Vales K., Stuchlik A. (2014). Spatial reversal learning in chronically sensitized rats and in undrugged sensitized rats with dopamine d2-like receptor agonist quinpirole. Front. Behav. Neurosci. 8:122. 10.3389/fnbeh.2014.00122 PubMed DOI PMC

Hynd M. R., Scott H. L., Dodd P. R. (2004). Differential expression of N-methyl-D-aspartate receptor NR2 isoforms in Alzheimer’s disease. J. Neurochem. 90: 913–919. 10.1111/j.1471-4159.2004.02548.x PubMed DOI

Kawakami R., Shinohara Y., Kato Y., Sugiyama H., Shigemoto R., Ito I. (2003). Asymmetrical allocation of NMDA receptor ε2 subunits in hippocampal circuitry. Science 300, 990–994. 10.1126/science.1082609 PubMed DOI

Kristofikova Z., Ricny J., Ort M., Ripova D. (2010). Aging and lateralization of the rat brain on a biochemical level. Neurochem. Res. 35, 1138–1146. 10.1007/s11064-010-0165-8 PubMed DOI

Kristofikova Z., Stastny F., Bubenikova V., Druga R., Klaschka J., Spaniel F. (2004). Age- and sex-dependent laterality of rat hippocampal system in relation to animal models of neurodevelopmental and neurodegenerative disorders. Neurochem. Res. 29, 671–680. 10.1023/b:nere.0000018837.27383.ff PubMed DOI

Kubík S., Fenton A. A. (2005). Behavioral evidence that segregation and representation are dissociable hippocampal functions. J. Neurosci. 25, 9205–9212. PubMed PMC

Lecanu L., Papadopoulos V. (2013). Modeling Alzheimer’s disease with non-transgenic rat models. Alzheimers. Res. Ther. 5:17. 10.1186/alzrt171 PubMed DOI PMC

Lecanu L., Greeson J., Papadopoulos V. (2006). Beta-amyloid and oxidative stress jointly induce neuronal death, amyloid deposits, gliosis and memory impairment in the rat brain. Pharmacology 76, 19–33. 10.1159/000088929 PubMed DOI

Lobellova V., Entlerova M., Svojanovska B., Hatalova H., Prokopova I., Petrásek T., et al. (2013). Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: a dose-response study. Behav. Brain Res. 246, 55–62. 10.1016/j.bbr.2013.03.006 PubMed DOI

Morris R. G. M. (1981). Spatial localization does not require the presence of local cues. Learn Motiv. 260, 239–260. 10.1016/0023-9690(81)90020-5 DOI

Pascual J., Fontán A., Zarranz J. J., Berciáno J., Flórez J., Pazos A. (1991). High-affinity choline uptake carrier in Alzheimer’s disease: implications for the cholinergic hypothesis of dementia. Brain Res. 552, 170–174. 10.1016/0006-8993(91)90676-m PubMed DOI

Petrásek T., Prokopova I., Bahnik S., Schonig K., Berger S., Vales K., et al. (2014a). Nogo-A downregulation impairs place avoidance in the Carousel maze but not spatial memory in the Morris water maze. Neurobiol. Learn Mem. 107, 42–49. 10.1016/j.nlm.2013.10.015 PubMed DOI

Petrásek T., Prokopova I., Sladek M., Weissova K., Vojtechova I., Bahnik S., et al. (2014b). Nogo-a-deficient transgenic rats show deficits in higher cognitive functions, decreased anxiety and altered circadian activity patterns. Front. Behav. Neurosci. 8: 90. 10.3389/fnbeh.2014.00090 PubMed DOI PMC

Phillips W. A., Silverstein S. M. (2003). Convergence of biological and psychological perspectives on cognitive coordination in schizophrenia. Behav. Brain Sci. 26, 65–82. 10.1017/s0140525x0328002x PubMed DOI

Piaceri I., Nacmias B., Sorbi S. (2013). Genetics of familial and sporadic Alzheimer’s disease. Front. Biosci. (Elite Ed). 5, 167–177. 10.2741/e605 PubMed DOI

Reiman E. M. (2014). Alzheimer’s disease and other dementias: advances in 2013. Lancet. Neurol. 13, 3–5. 10.1016/S1474-4422(13)70257-6 PubMed DOI

Rodríguez-Puertas R., Pazos A., Zarranz J. J., Pascual J. (1994). Selective cortical decrease of high-affinity choline uptake carrier in Alzheimer’s disease: an autoradiographic study using [3H]hemicholinium-3. J. Neural. Transm. 8, 161–169. 10.1007/bf02260937 PubMed DOI

Rossor M. N., Newman S., Frackowiak R. S., Lantos P., Kennedy A. M. (1993). Alzheimer’s disease families with amyloid precursor protein mutations. Ann. N. Y. Acad. Sci. 695: 198–202. 10.1016/b978-012286965-5/50006-6 PubMed DOI

Sabbagh J. J., Kinney J. W., Cummings J. L. (2013). Animal systems in the development of treatments for Alzheimer’s disease: challenges, methods and implications. Neurobiol. Aging 34, 169–183. 10.1016/j.neurobiolaging.2012.02.027 PubMed DOI

Schuitemaker A., Dik M. G., Veerhuis R., Scheltens P., Schoonenboom N. S., Hack C. E., et al. . (2009). Inflammatory markers in AD and MCI patients with different biomarker profiles. Neurobiol. Aging 30, 1885–1889. 10.1016/j.neurobiolaging.2008.01.014 PubMed DOI

Sims N. R., Bowen D. M., Allen S. J., Smith C. C., Neary D., Thomas D. J., Davison A. N. (1983). Presynaptic cholinergic dysfunction in patients with dementia. J. Neurochem. 40, 503–509. 10.1111/j.1471-4159.1983.tb11311.x PubMed DOI

Slotkin T. A., Seidler F. J., Crain B. J., Bell J. M., Bissette G., Nemeroff C. B. (1990). Regulatory changes in presynaptic cholinergic function assessed in rapid autopsy material from patients with Alzheimer disease: implications for etiology and therapy. Proc. Natl. Acad. Sci. USA 87, 2452–2455. 10.1073/pnas.87.7.2452 PubMed DOI PMC

Spires-Jones T. L., Hyman B. T. (2014). The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82, 756–771. 10.1016/j.neuron.2014.05.004 PubMed DOI PMC

Stuchlik A. (2014). Dynamic learning and memory, synaptic plasticity and neurogenesis: an update. Front. Behav. Neurosci. 8:106. 10.3389/fnbeh.2014.00106 PubMed DOI PMC

Stuchlik A., Vales K. (2008). Role of alpha1- and alpha2-adrenoceptors in the regulation of locomotion and spatial behavior in the active place avoidance task: a dose-response study. Neurosci. Lett. 433, 235–240. 10.1016/j.neulet.2008.01.013 PubMed DOI

Stuchlik A., Kubik S., Vlcek K., Vales K. (2014). Spatial navigation: implications for animal models, drug development and human studies. Physiol. Res. 63, S237–S249. PubMed

Stuchlik A., Petrásek T., Prokopová I., Holubová K., Hatalová H., Valeš K., et al. (2013). Place avoidance tasks as tools in the behavioral neuroscience of learning and memory. Physiol. Res. 62, S1–S19. PubMed

Stuchlik A., Rehakova L., Rambousek L., Svoboda J., Vales K. (2007a). Manipulation of D2 receptors with quinpirole and sulpiride affects locomotor activity before spatial behavior of rats in an active place avoidance task. Neurosci. Res. 58, 133–139. 10.1016/j.neures.2007.02.006 PubMed DOI

Stuchlik A., Rehakova L., Telensky P., Vales K. (2007b). Morris water maze learning in Long-Evans rats is differentially affected by blockade of D1-like and D2-like dopamine receptors. Neurosci. Lett. 422, 169–174. 10.1016/j.neulet.2007.06.012 PubMed DOI

Wenk G. L. (2003). Neuropathologic changes in Alzheimer’s disease. J. Clin. Psychiatry 64, 7–10. PubMed

Wesierska M., Dockery C., Fenton A. A. (2005). Beyond memory, navigation and inhibition: behavioral evidence for hippocampus-dependent cognitive coordination in the rat. J. Neurosci. 25, 2413–2419. 10.1523/jneurosci.3962-04.2005 PubMed DOI PMC

Ye X., Tai W., Zhang D. (2012). The early events of Alzheimer’s disease pathology: from mitochondrial dysfunction to BDNF axonal transport deficits. Neurobiol. Aging 33, 1122.e1–1122.e10. 10.1016/j.neurobiolaging.2011.11.004 PubMed DOI

Acute and Chronic Sleep Deprivation-Related Changes in N-methyl-D-aspartate Receptor-Nitric Oxide Signalling in the Rat Cerebral Cortex with Reference to Aging and Brain Lateralization

The McGill Transgenic Rat Model of Alzheimer's Disease Displays Cognitive and Motor Impairments, Changes in Anxiety and Social Behavior, and Altered Circadian Activity

Mnemonic and behavioral effects of biperiden, an M1-selective antagonist, in the rat