title: Impairment of synaptic development in the hippocampus of diabetic Goto-Kakizaki rats.
abstract: Insulin receptor signaling has been shown to regulate essential aspects of CNS function such as synaptic plasticity and neuronal survival. To elucidate its roles during CNS development in vivo, we examined the synaptic and cognitive development of the spontaneously diabetic Goto-Kakizaki (GK) rats in the present study. GK rats are non-obese models of type 2 diabetes established by selective inbreeding of Wistar rats based on impaired glucose tolerance. Though they start exhibiting only moderate hyperglycemia without changes in plasma insulin levels from 3 weeks postnatally, behavioral alterations in the open-field as well as significant impairments in memory retention compared with Wistar rats were observed at 10 weeks and were worsened at 20 weeks. Alterations in insulin receptor signaling and signs of insulin resistance were detected in the GK rat hippocampus at 3 weeks, as early as in other insulin-responsive peripheral tissues. Significant reduction of an excitatory postsynaptic scaffold protein, PSD95, was found at 5w and later in the hippocampus of GK rats due to the absence of a two-fold developmental increase of this protein observed in Wistar control rats between 3 and 20w. In the GK rat hippocampus, NR2A which is a NMDA receptor subunit selectively anchored to PSD95 was also reduced. In contrast, both NR2B and its anchoring protein, SAP102, showed similar developmental profiles in Wistar and GK rats with expression peaks at 2 and 3w. The results suggest that early alterations in insulin receptor signaling in the GK rat hippocampus may affect cognitive performance by suppressing synaptic maturation.
authors.affiliation: Department of Chemistry & Biological Science, School of Science & Engineering, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa, 252-5258, Japan. Electronic address: ukey1025pine@gmail.com.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsunaga
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Aichi 468-8503, Japan. Electronic address: tnegishi@meijo-u.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Negishi
authors.affiliation: Department of Chemistry & Biological Science, School of Science & Engineering, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa, 252-5258, Japan. Electronic address: akinori.h0209@gmail.com.
authors.forename: Akinori
authors.initials: A
authors.lastname: Hatakeyama
authors.affiliation: Department of Chemistry & Biological Science, School of Science & Engineering, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa, 252-5258, Japan. Electronic address: fuji.tv0918@gmail.com.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kawagoe
authors.affiliation: Department of Chemistry & Biological Science, School of Science & Engineering, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa, 252-5258, Japan. Electronic address: sawanoerika@nagasaki-u.ac.jp.
authors.forename: Erika
authors.initials: E
authors.lastname: Sawano
authors.affiliation: Department of Chemistry & Biological Science, School of Science & Engineering, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa, 252-5258, Japan. Electronic address: tashilein@chem.aoyama.ac.jp.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tashiro
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D021983:Cyclophilins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D007328:Insulin / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008124:Locomotion / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D059645:Mutation Rate; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D018709:Statistics, Nonparametric; D013569:Synapses / Q000378:metabolism / Q000473:pathology*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D050598:Vesicular Glutamate Transport Protein 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; D021983:Cyclophilins