Is rat with antisense-induced in vivo knockdown of a spine protein drebrin A a model for schizophrenia?

Makoto Saji

Abstract

Drebrin A located in dendritic spines regulates their morphological changes and plays a role in the synaptic plasticity via spine function. Reduced drebrin A has been found in the brain of patients with Alzheimer�fs disease or Down�fs syndrome. To examine whether the down-regulation of drebrin A protein levels causes deficits in higher brain function, such as memory formation or cognition, we performed antisense-induced knockdown of drebrin A expression in rat brain by using an HVJ-liposome gene transfer technique. We investigated the effects of drebrin in vivo knockdown on acquisition of spatial memory in a hidden platform task in water maze, retention of spatial memory in a probe trial in water maze, sensorimotor gating including cognitive function in a pre-pulse-inhibition test, adaptive behaviors in an open-field test, and sensitivity to psychostimulant in an amphetamine-induced locomotor response. Rats with drebrin A in vivo knockdown displayed a stronger preference for a previous event due to perseverative behavior, impaired pre-pulse inhibition, increased locomotor activity, anxiety-like behavior, and an hypersensitivity to psychostimulant, suggesting modeling behaviors related to schizophrenia. These findings indicated that decreased drebrin A produces deficits in cognitive function but not in spatial memory formation, probably via hypofunction of dendritic spines. We conclude that the drebrin A in vivo knockdown rat may be a good animal model for positive symptom of schizophrenia.

Kobayashi S, Ohno K, Iwakuma M, Kaneda Y, and Saji M. Synaptotagmin I hypothalamic knockdown prevents amygdaloid seizure-induced damage of hippocampal neurons but not of entorhinal neurons. Neurosci Res, 44: 455-465(2002).

Iwakuma M, Anzai T, Kobayashi S, Ogata M, Kaneda Y, Ohno K, and Saji M. Antisense in vivo knockdown of synaptotagmin I and synapsin I by HVJ-liposome mediated gene transfer modulates ischemic injury of hippocampus in opposing ways. Neurosci Res, 45:285-296(2003).

Inada K, Ishigooka J, Anzai T, Suzuki E, Miyaoka H, and Saji M. Antisense hippocampal knockdown of NMDA-NR1 by HVJ-liposome vector induces deficit of prepulse inhibition but not of spatial memory. Neurosci Res, 45: 473-481(2003).

Anzai T, Tsuzuki K, Yamada N, Hayashi T, Iwakuma M, Inada K, Kameyama K, Hoka S, and Saji M. Overexpression of Ca2+-permeable AMPA receptor promotes delayed cell death of hippocampal CA1 neurons following transient forebrain ischemia. Neurosci Res, 46: 41-51(2003).

Noda K, Anzai T, Ogata M, Akita H, Ogura T and Saji M. Antisense knockdown of spinal-mGluR1 reduced sustained phase of formalin-induced nociceptive responses

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