Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory

Abstract

The insulin-regulated glucose transporter-4 (GluT4) is critical for insulin-and contractile-mediated glucose uptake in skeletal muscle. GluT4 is also expressed in some hippocampal neurons, but its functional role in the brain is unclear. Several established molecular modulators of memory processing regulate hippocampal GluT4 trafficking and hippocampal memory formation is limited by both glucose metabolism and insulin signaling. Therefore, we hypothesized that hippocampal GluT4 might be involved in memory processes. Here, we show that, in male rats, hippocampal GluT4 translocates to the plasma membrane after memory training and that acute, selective intrahippocampal inhibition of GluT4-mediated glucose transport impaired memory acquisition, but not memory retrieval. Other studies have shown that prolonged systemic GluT4 blockade causes insulin resistance. Unexpectedly, we found that prolonged hippocampal blockade of glucose transport through GluT4-upregulated markers of hippocampal insulin signaling prevented task-associated depletion of hippocampal glucose and enhanced both working and short-term memory while also impairing long-term memory. These effects were accompanied by increased expression of hippocampal AMPA GluR1 subunits and the neuronal GluT3, but decreased expression of hippocampal brain-derived neurotrophic factor, consistent with impaired ability to form long-term memories. Our findings are the first to show the cognitive impact of brain GluT4 modulation. They identify GluT4 as a key regulator of hippocampal memory processing and also suggest differential regulation of GluT4 in the hippocampus from that in peripheral tissues.

Glucose metabolism in nerve terminals

“…2E), thereby highlighting the crucial role of glycolytic regulation in synaptic function. Consistent with our Glut4 study, a new report indicates that hippocampal Glut4 translocates to the plasma membrane after memory training and is involved in long-term memory formation[21]. …”

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

“…These regions include the basal forebrain, hippocampus, amygdala and, to lesser degrees, the cerebral cortex and cerebellum 77 . Activation by insulin induces GLUT4 translocation to the neuron cell membrane via an AKT-dependent mechanism 78,79 and is thought to improve glucose flux into neurons during periods of high metabolic demand, such as during learning 80 . Interestingly, GLUT4 is also expressed in the hypothalamus 81 , a key area for metabolic control.…”

Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters

“…Alterations in GLUT function can occur in acquired diseases, as well. Diabetic conditions can affect both GLUT localization (Bakirtzi et al, 2009) and activity (for example, GLUT4 activity in the periphery is impaired under type 2 diabetes) (Pearson-Leary and McNay, 2016); however, expression levels of GLUTs in glial or neuronal cells does not appear to be altered by diabetic conditions (de Preux Charles et al,2010; Hur et al, 2011; Pande et al, 2011). Schwann cells, which metabolically support axons in the PNS, are crucial cell types in the pathogenesis of diabetic neuropathy (Zenker et al, 2013; Mizisin, 2014; Feldman et al, 2017; Goncalves et al, 2017).…”