title: Reduction in NPY-positive neurons and dysregulation of excitability in young senescence-accelerated mouse prone 8 (SAMP8) hippocampus precede the onset of cognitive impairment.
abstract: The senescence-accelerated mouse prone 8 (SAMP8) strain is considered a neurodegeneration model showing age-related cognitive deficits with little physical impairment. Young SAMP8 mice, however, exhibit signs of disturbances in development such as marked hyperactivity and reduced anxiety well before the onset of cognitive impairment. As the key enzyme in local regulation of thyroid hormone (TH) signaling, type 2 deiodinase, was significantly reduced in the SAMP8 hippocampus relative to that of the normally aging SAM-resistant 1 (SAMR1), we used these two strains to compare the development of the hippocampal GABAergic system, which is known to be strongly affected by hypothyroidism. Among GABAergic components, neuronal K+ /Cl- co-transporter 2 was down-regulated in SAMP8 transiently at 2 weeks. Although distribution of total GABAergic neurons was similar in both strains, 22-30% reduction was observed in the neuropeptide Y (NPY)-positive subpopulation of GABAergic neurons in SAMP8. Electrophysiological studies on hippocampal slices obtained at 4 weeks revealed that epileptiform activity, induced by high-frequency stimulation, lasted four times longer in SAMP8 compared with SAMR1, indicating a dysregulation of excitability that may be linked to the behavioral abnormalities of young SAMP8 and to neurodegeneration later on in life. Local attenuation of TH signaling may thus impact the normal development of the GABAergic system.
authors.affiliation: Department of Chemistry & Biological Science, School of Science & Engineering, Aoyama Gakuin University, Sagamihara, Kanagawa, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Sawano
authors.affiliation: Department of Chemistry & Biological Science, School of Science & Engineering, Aoyama Gakuin University, Sagamihara, Kanagawa, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Iwatani
authors.affiliation: Department of Neuroscience, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Tominaga-Yoshino
authors.affiliation: Department of Neuroscience, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ogura
authors.affiliation: Department of Chemistry & Biological Science, School of Science & Engineering, Aoyama Gakuin University, Sagamihara, Kanagawa, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tashiro
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D003072:Cognition Disorders / Q000523:psychology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D055724:Electrophysiological Phenomena; D006624:Hippocampus / Q000473:pathology*; D007453:Iodide Peroxidase / Q000235:genetics; D007859:Learning Disabilities / Q000235:genetics / Q000523:psychology; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000523:psychology; D051379:Mice; D019636:Neurodegenerative Diseases / Q000523:psychology; D009474:Neurons / Q000473:pathology*; D009478:Neuropeptide Y / Q000378:metabolism*; D010766:Phosphorylation; D027981:Symporters / Q000378:metabolism; D013963:Thyroid Hormones / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology; D000096922:K Cl- Cotransporters
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D007453:Iodide Peroxidase; D009478:Neuropeptide Y; D027981:Symporters; D013963:Thyroid Hormones; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters
keywords: GABA; NPY-positive neuron; SAMP8; deiodinase 2; epileptiform activity; hippocampus