Glucose Overload Inhibits Glutamatergic Synaptic Transmission: A Novel Role for CREB-Mediated Regulation of Synaptotagmins 2 and 4.

Cristian Ripoli,Salvatore Fusco,Claudio Grassi,Francesca Natale,Matteo Spinelli

doi:10.3389/fcell.2020.00810

Abstract

Glucose metabolism derangement is critically involved in the age-related memory loss but the underlying molecular mechanisms are still poorly understood. In a mouse model of type 1 diabetes we found memory impairment associated with inhibition of the transcription factor CREB and alteration of pre- and post-synaptic protein expression in the hippocampus. Accordingly, glucose excess negatively affected activity-dependent CREB phosphorylation and CREB-mediated mRNA expression of synaptic proteins in hippocampal primary neurons. Specifically, glucose excess inhibited the activity-dependent recruitment of CREB on the regulatory sequences of synaptotagmin (SYT) 2 and 4 promoters and the expression of SYT4 protein. As a result, high glucose affected both the frequency of miniature excitatory postsynaptic currents and NMDA receptor-mediated currents in autaptic hippocampal neuronal cultures. Collectively, our findings highlight novel mechanisms underlying hyperglycaemia-related memory loss, including CREB-dependent downregulation of synaptotagmin expression.

Highlights

In response to physiological stimuli and environmental conditions, the central nervous system undergoes functional and structural changes (Pascual-Leone et al, 2005)
We found that a well-established animal model of hyperglycaemia, i.e., the STZ-injected mice, exhibited memory deficits (Figure 1B) associated with molecular changes in the hippocampus including lower amounts of NMDA receptor subunits GluN1 and GluN2a (Figure 1C), reduced phosphorylation levels of memory-related transcription factor cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) (Figure 1C) and decreased expression of genes encoding for synaptic proteins regulating synaptic transmission and plasticity such as SYT2, SYT4 and BDNF (Figure 1D)
CREB is a pivotal hub in the activity-driven neuronal gene expression (Benito et al, 2011) and its activity has been reported to be critically reduced in the context of aging and age-associated brain diseases (Zuccato et al, 2001; Cui et al, 2006; Caccamo et al, 2010)

Summary

Introduction

In response to physiological stimuli and environmental conditions, the central nervous system undergoes functional and structural changes (Pascual-Leone et al, 2005). Glucose metabolism derangement and type 2 diabetes negatively impact on synaptic plasticity and cognitive functions through multiple mechanisms including oxidative stress, Glucose Overload Inhibits Synaptic Transmission endothelial dysfunctions, microglia activation and neurotrophin depletion (Kullmann et al, 2016; Duffy et al, 2019; Spinelli et al, 2019). The transcription factor cAMP response element-binding protein (CREB) has been widely investigated as a metabolic sensor and regulator of glucose homeostasis in liver and fat tissue (Altarejos and Montminy, 2011), and as a master switch of Ca2+ and neurotrophin-triggered transcriptional programs regulating neuronal differentiation, survival, and plasticity in central and peripheral nervous systems (Riccio et al, 1999; Finkbeiner, 2000, Mantamadiotis et al, 2002). We identified synaptotagmin 2 and 4 (SYT2 and SYT4, respectively) as novel glucose-responsive CREB target genes involved in hyperglicaemia-dependent impairment of synaptic function

Methods

Results

Conclusion