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The Journal of Neuroscience, July 13, 2005, 25(28):6539-6549; doi:10.1523/JNEUROSCI.0283-05.2005

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Neurobiology of Disease
Neurocognitive and Psychotiform Behavioral Alterations and Enhanced Hippocampal Long-Term Potentiation in Transgenic Mice Displaying Neuropathological Features of Human -Mannosidosis

Rudi D'Hooge,¹ Renate Lüllmann-Rauch,³ Tom Beckers,² Detlef Balschun,⁵ Michael Schwake,⁴ Karina Reiss,⁴ Kurt von Figura,⁶ and Paul Saftig⁴

¹Laboratory of Biological Psychology and ²Centre for Learning Psychology and Experimental Psychopathology, University of Leuven, B-3000 Leuven, Belgium, ³Anatomical Institute and ⁴Biochemical Institute, University of Kiel, D-24098 Kiel, Germany, ⁵Leibniz Institute for Neurobiology, D-39118 Magdeburg, Germany, and ⁶Biochemistry and Molecular Cell Biology, University of Göttingen, D-37073 Göttingen, Germany

Mice with -mannosidase gene inactivation provide an experimental model for -mannosidosis, a lysosomal storage disease with severe neuropsychological and psychopathological complications. Neurohistological alterations in these mice were similar to those in patients and included vacuolations and axonal spheroids in the CNS and peripheral nervous system. Vacuolation was most prominent and evenly distributed in neuronal perikarya of the hippocampal CA2 and CA3 regions, whereas CA1 and dentate gyrus were weakly or not affected. Field potential recordings from CA1 region in hippocampal slices showed enhanced theta burst-induced long-term potentiation (LTP) in -mannosidase-deficient mice. Longitudinal assessment in age-matched -mannosidase-deficient and wild-type littermates, using an extended test battery, demonstrated a neurocognitive and psychotiform profile that may relate to the psychopathological alterations in clinical -mannosidosis. Brainstem auditory-evoked potentials and basic neuromotor abilities were not impaired and did not deteriorate with age. Exploratory and conflict tests revealed consistent decreases in exploratory activity and emotional blunting in the knock-out group. -Mannosidosis mice were also impaired in aversively motivated learning and acquisition of signal-shock associations. Acquisition and reversal learning in the water maze task, passive avoidance learning in the step-through procedure, as well as emotional response conditioning in an operant procedure were all impaired. Acquisition or shaping of an appetitive instrumental conditioning task was unchanged. Appetitive odor discrimination learning was only marginally impaired during shaping, whereas both the discrimination and reversal subtasks were normal. We propose that prominent storage and enhanced LTP in hippocampus have contributed to these specific behavioral alterations in -mannosidase-deficient mice.

Key words: behavior; degeneration; metabolism; neuropathology; storage; learning and memory; knock-out mice

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Received Jan 20, 2005; revised May 3, 2005; accepted May 31, 2005.

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