Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4

Abstract

The insulin-regulated glucose transporter, GluT4, is a key molecule in peripheral insulin signaling. Although GluT4 is abundantly expressed in neurons of specific brain regions such as the hippocampus, the functional role of neuronal GluT4 is unclear. Here, we used pharmacological inhibition of GluT4-mediated glucose uptake to determine whether GluT4 mediates insulin-mediated glucose uptake in the hippocampus. Consistent with previous reports, we found that glucose utilization increased in the dorsal hippocampus of male rats during spontaneous alternation (SA), a hippocampally-mediated spatial working memory task. We previously showed that insulin signaling within the hippocampus is required for processing this task, and that administration of exogenous insulin enhances performance. At baseline levels of hippocampal insulin, inhibition of GluT4-mediated glucose uptake did not affect SA performance. However, inhibition of an upstream regulator of GluT4, Akt, did impair SA performance. Conversely, when a memory-enhancing dose of insulin was delivered to the hippocampus prior to SA-testing, inhibition of GluT4-mediated glucose transport prevented cognitive enhancement. These data suggest that baseline hippocampal cognitive processing does not require functional hippocampal GluT4, but that cognitive enhancement by supra-baseline insulin does. Consistent with these findings, we found that in neuronal cell culture, insulin increases glucose utilization in a GluT4-dependent manner. Collectively, these data demonstrate a key role for GluT4 in transducing the procognitive effects of elevated hippocampal insulin.

Mediterranean Diet Nutrients to Turn the Tide against Insulin Resistance and Related Diseases

“…However, peripheral IR is strongly related to brain dysfunction, either due to reduced insulin transport into the brain [115] or to altered local insulin receptor sensitivity and activation [116]. Notwithstanding a marginal role in neuronal glucose uptake under basal conditions, as it mostly occurs in an insulin-independent manner, insulin positively regulates the normal brain function, particularly by enhancing the spatial working memory via the insulin-sensitive glucose transporter GLUT-4 [117]. In line with these considerations, cyanidin-3-O-glucopyranoside, by acting as a potent natural agonist for PPARγ with peripheral and central insulin-sensitizing effects, has been shown not only to reduce liver fat [118] and fasting glucose concentrations [107] of treated animals, but also to increase cerebral glucose uptake [107].…”

Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

“…At the same time, as the implication of IR in the regulation of energy and glucose homeostasis in the brain has been revisited, these processes are now not considered to be entirely insulin‐independent, and compromised glucose metabolism in the brain resulting from deficient IR function is regarded as another critical factor in the risk for neuropsychiatric disorders. In particular, glucose uptake in the hippocampus was shown to be dependent on IR‐stimulated translocation of the glucose transporter GLUT4 to the plasma membrane . This recently discovered mechanism is likely to play a role with other glucose transporters, such as GLUT1, GLUT3, and GLUT5, which are expressed in astrocytes, neurons, and microglia, respectively …”

“…In particular, glucose uptake in the hippocampus was shown to be dependent on IR‐stimulated translocation of the glucose transporter GLUT4 to the plasma membrane . This recently discovered mechanism is likely to play a role with other glucose transporters, such as GLUT1, GLUT3, and GLUT5, which are expressed in astrocytes, neurons, and microglia, respectively …”

Does shuttling of glycogen‐derived lactate from astrocytes to neurons take place during neurotransmission and memory consolidation?

“…Neuronal glycolysis, not utilization of extracellular lactate (derived from astrocytic glucose or glycogen), is upregulated during stimulation of hippocampal slices in vitro and whisker barrel cortex in vivo (Diaz‐Garcia et al, ; Yellen, ). In addition, mobilization of the glucose transporter GLUT4 from internal stores to the presynaptic membrane is required to support synaptic vesicle cycling (Ashrafi & Ryan, ; Ashrafi, Wu, Farrell, & Ryan, ) and memory formation (Pearson‐Leary, Jahagirdar, Sage, & McNay, ; Pearson‐Leary & McNay, ). These studies support the conclusion that there is increased neuronal use of blood‐borne glucose during activation and memory consolidation.…”