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.

Dynamic SAP102 expression in the hippocampal subregions of rats and APP/PS1 mice of various ages

“…Under observation with a high-powered microscope, SAP102 was intensely expressed in the cytoplasms throughout the process areas but not in the nuclei (Figs 1-4). The fluorescence intensities of SAP102 in the hippocampal subfields CA1, CA3 and DG increased gradually with age from P0 to P56; in adulthood, SAP102 maintained relatively higher levels from P56 to P8 m. In aged rats (P20 m), SAP102 unexpectedly displayed no significant decrease in the CA1 and DG regions (P > 0.05) but did decrease in the CA3 subregion (P < 0.05, P20 m vs. P8 m), which contrasted with the results of previous studies (Sans et al 2000;Matsunaga et al 2016).…”

“…Our data herein showed that SAP102 was highly expressed in the rat hippocampus from P56 to P8 m and displayed no significant decreases in the CA1 and DG regions at P20 m. Numerous reports have demonstrated that SAP102 is expressed in the hippocampus at young ages and is then mostly replaced by PSD95 in later stages of life (Sans et al 2000;Elias et al 2006;Murata & Constantine-Paton, 2013). Matsunaga reported that the SAP102 level in the Wistar rat hippocampus increased from P35 to P5 m (Matsunaga et al 2016), which is unlike the reduced level of SAP102 expression from P35 to P6 m found by Sans et al (2000). In humans, researchers examined SAP102 expression in the brain tissues of humans aged 57-87 years, finding that SAP102 maintained relatively higher expression levels in the inferior temporal lobe, occipital lobe and hippocampus (Proctor et al 2010).…”

“…Matsunaga reported that the SAP102 level in the Wistar rat hippocampus increased from P35 to P5 m (Matsunaga et al. ), which is unlike the reduced level of SAP102 expression from P35 to P6 m found by Sans et al. ().…”

Retinal Deficits Precede Cognitive and Motor Deficits in a Rat Model of Type II Diabetes

“…Other assays may be more sensitive and could detect changes at earlier timepoints. However, previous studies in GK rats only revealed deficits at later times, including deficits in novel object recognition observed at 24 weeks of age, 48 deficits in memory retention observed at 10 weeks, 49 and deficits in olfactory memory at 6 to 10 months. 35…”

“…Indeed, early changes in insulin receptor signaling in the hippocampus were shown to inhibit synaptic maturation and potentially cause cognitive deficits in the GK rat. 49 In addition, decreased inhibition from amacrine cells has been proposed to increase rod bipolar cell signaling in the diabetic retina, 51 suggesting that amacrine cells could be investigated in the GK rat as a target for synaptic change during hyperglycemia in retinal development. Contrary to our results, other groups have reported reduced ERG amplitudes in the GK rat.…”