Animal model of dementia induced by entorhinal synaptic damage and partial restoration of cognitive deficits by BDNF and carnitine.
A rat dementia model with cognitive deficits was generated by synapse-specific lesions using botulinum neurotoxin (BoNTx) type B in the entorhinal cortex. To detect cognitive deficits, different tasks were needed depending upon the age of the model animals. Impaired learning and memory with lesions were observed in adult rats using the Hebb-Williams maze, AKON-1 maze and a continuous alternation task in T-maze. Cognitive deficits in lesioned aged rats were detected by a continuous alternation and delayed non-matching-to-sample tasks in T-maze. Adenovirus-mediated BDNF gene expression enhanced neuronal plasticity, as revealed by behavioral tests and LTP formation. Chronic administration of carnitine over time pre- and post-lesions seemed to partially ameliorate the cognitive deficits caused by the synaptic lesion. The carnitine-accelerated recovery from synaptic damage was observed by electron microscopy. These results demonstrate that the BoNTx-lesioned rat can be used as a model for dementia and that cognitive deficits can be alleviated in part by BDNF gene transfer or carnitine administration.
Ando
Susumu
S
Neuronal Function Research Group, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan. andos@tmig.or.jp
Kobayashi
Satoru
S
Waki
Hatsue
H
Kon
Kazuo
K
Fukui
Fumiko
F
Tadenuma
Tomoko
T
Iwamoto
Machiko
M
Takeda
Yasuo
Y
Izumiyama
Naotaka
N
Watanabe
Kazutada
K
Nakamura
Hiroaki
H
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D002331:Carnitine / Q000494:pharmacology* / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D005822:Genetic Vectors / Q000627:therapeutic use; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008854:Microscopy, Electron; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D050683:R-SNARE Proteins; D051381:Rats; D011916:Rats, Inbred F344; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D008565:Membrane Proteins; D050683:R-SNARE Proteins; D011993:Recombinant Fusion Proteins; D019274:Botulinum Toxins, Type A; D002331:Carnitine