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

Abstract

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.

Tau-Induced Defects in Synaptic Plasticity, Learning, and Memory Are Reversible in Transgenic Mice after Switching Off the Toxic Tau Mutant

“…A 150 cm circular pool was filled with water opacified with nontoxic white paint and kept at 26°C as described previously (D'Hooge et al, 2005). A 15-cm-round platform was hidden 1 cm beneath the surface of the water at a fixed position.…”

Multi-system disorders of glycosphingolipid and ganglioside metabolism

“…The application of long-term potentiation (LTP) analyses has provided insight into the pathogenesis and levels of neural involvement of the GSL and lysosomal disorders ( 193,212,287 ). For such analyses, a constant level of presynaptic stimulation is converted to a large postsynaptic output, i.e., LTP, a leading experiment to study learning and memory ( 288 ).…”

Vesicular Glutamate Transporter VGLUT2 Expression Levels Control Quantal Size and Neuropathic Pain

“…Spatial memory abilities were examined in the standard hidden-platform acquisition and retention and reversal learning versions of the Morris maze. A 150 cm circular pool was filled with water, made opaque with nontoxic white paint, and kept at 26°C as described previously (Morris, 1989;D'Hooge et al, 2005). A 15 cm round platform was hidden 1 cm beneath the surface of the water at a fixed position.…”