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The Journal of Neuroscience, August 26, 2009, 29(34):10741-10749; doi:10.1523/JNEUROSCI.1065-09.2009

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Neurobiology of Disease
Age-Dependent Impairment of Cognitive and Synaptic Function in the htau Mouse Model of Tau Pathology

Manuela Polydoro,¹ Christopher M. Acker,² Karen Duff,³ Pablo E. Castillo,¹ and Peter Davies^1,2,4

¹Dominick P. Purpura Department of Neuroscience and ²Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, ³Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Departments of Neurology and Pathology, Columbia University College of Physicians and Surgeons, Columbia University, New York, New York 10032, and ⁴Litwin-Zucker Research Center for the Study of Alzheimer Disease, The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York 11030

Correspondence should be addressed to Peter Davies or Pablo E. Castillo at the above addresses, Email: davies{at}aecom.yu.edu or Email: pcastill{at}aecom.yu.edu

A hallmark feature of Alzheimer's disease pathology is the presence of neurofibrillary tangles (NFTs), which are intracellular aggregates of conformationally abnormal and hyperphosphorylated tau. The presence of NFTs in the forebrain is associated with impairments of cognitive function, supporting a central role for tau in dementia. The significance of the accumulation of NFTs for neuronal and cognitive function is still obscure. It is possible that NFTs disrupt synaptic transmission and plasticity, leading to memory deficits and cognitive malfunction. To elucidate the relationship between the development of tau pathology and synaptic and cognitive functions, we performed behavioral tests and electrophysiological experiments in the htau mouse. Here we report age-dependent cognitive and physiological impairments in htau mice that preceded neurodegeneration. Twelve-month-old htau mice with moderate tau pathology, but not 4-month-old mice with early-stage tau pathology, presented cognitive deficits in an object recognition memory task in which the visual recognition memory of a novel object was disrupted. Moreover, only 12-month-old htau mice exhibit spatial memory deficits, as indicated by the impaired performance in the Morris water maze. In addition, we report that basal synaptic transmission and induction of long-term potentiation with high-frequency stimulation, but not theta burst stimulation, is perturbed in hippocampal CA1 region of old but not young htau mice. Our results suggest that tau pathology may underlie an age-dependent learning impairment through disruption of synaptic function.

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Received March 4, 2009; revised July 2, 2009; accepted July 7, 2009.

Correspondence should be addressed to Peter Davies or Pablo E. Castillo at the above addresses, Email: davies{at}aecom.yu.edu or Email: pcastill{at}aecom.yu.edu

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