RT Journal Article
SR Electronic
T1 Neurocognitive and Psychotiform Behavioral Alterations and Enhanced Hippocampal Long-Term Potentiation in Transgenic Mice Displaying Neuropathological Features of Human α-Mannosidosis
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6539
OP 6549
DO 10.1523/JNEUROSCI.0283-05.2005
VO 25
IS 28
A1 Rudi D'Hooge
A1 Renate Lüllmann-Rauch
A1 Tom Beckers
A1 Detlef Balschun
A1 Michael Schwake
A1 Karina Reiss
A1 Kurt von Figura
A1 Paul Saftig
YR 2005
UL http://www.jneurosci.org/content/25/28/6539.abstract
AB Mice with α-mannosidase gene inactivation provide an experimental model for α-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 α-mannosidase-deficient mice. Longitudinal assessment in age-matched α-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 α-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. α-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 α-mannosidase-deficient mice.