Synaptic Adaptation to Repeated Hypoglycemia Depends on the Utilization of Monocarboxylates in Guinea Pig Hippocampal Slices

Abstract

This report provides in vitro evidence that synaptic activity becomes resistant to repeated hypoglycemia, i.e., hypoglycemic synaptic adaptation occurs. Synaptic function was estimated by the amplitude of the postsynaptic population spike (PS) recorded in the granule cell layer of guinea pig hippocampal slices. ATP, phosphocreatine (PCr), glycogen, and glucose concentrations were measured to investigate energy metabolism homeostasis. Glucose deprivation produced a complete elimination of the PS amplitude, with a 50% inhibition by 10.6 min, and a ϳ15% reduction in ATP and PCr concentrations. Low-glucose (0.5-1 mmol/l) medium gradually depressed the PS. After recovery from glucose depletion, repeated glucose deprivation produced a slowly developing depression of PS, with a 50% inhibition by 36.5 min. However, ATP and PCr concentrations were maintained. Incubation in secondary low-glucose medium maintained PS amplitude. Hippocampal glycogen and glucose concentrations promptly decreased during repeated glucose deprivation, indicating that glycogenolysis does not fuel synaptic adaptation to repeated hypoglycemia. Synaptic function during repeated glucose depletion was reversibly depressed by addition of ␣-cyano-4-hydroxycinnamic acid or 3-isobutyl-1-methylxanthine, inhibitors of the monocarboxylate transporter. Replacement of extracellular glucose with Na-lactate or Na-pyruvate sustained synaptic transmission after transient glucose depletion. These results indicate that synaptic utilization of monocarboxylates sustains hypoglycemic synaptic adaptation. Diabetes 51:430 -438, 2002 P rospective studies of diabetes and its complications clearly demonstrate that glycemic control prevents or delays several long-term complications of the disease. However, attempts to achieve near-normal blood glucose levels increase the risk of hypoglycemia, the most common and serious iatrogenic morbidity in patients with diabetes. Because glucose is the principal metabolic fuel of the brain, acute hypoglycemia can cause profound but reversible autonomic and neuroglycopenic symptoms (1). Hypoglycemia induces counterregulatory hormonal responses, which produce sympathetic symptoms. Neurobehavioral deficits associated with insulin-induced hypoglycemia frequently arise on tasks that require sustained attention, rapid decision making, analysis of complex visual stimuli, mental flexibility, and memory of recently learned information (1,2).The main defense against severe hypoglycemia is the subjective recognition of the onset of falling glucose levels. Some diabetic patients lose this symptomatic awareness and show reduced neuroendocrine responses to hypoglycemia, which is defined as hypoglycemia unawareness. In response to repeated hypoglycemia, the glucose threshold at which the brain detects hypoglycemia and triggers neurohumoral responses is shifted downward in nondiabetic individuals and in patients with diabetes (3-5). Glucose-sensing areas of the brain, presumably including the ventromedial hypothalamus, are responsible for the detection...

Effects of relative hypoglycemia on LTP and NADH imaging in rat hippocampal slices

“…The reversible loss of fEPSP induced by 30 min of aglycemia at 35°C [36] becomes irreversible in our experiments (also at 35°C) by 60 min. Other studies using submerged slices demonstrate low glucose can induce decreased fEPSP slope at a variety of temperatures [10,36,45].…”

“…The rate of fEPSP loss during hypoglycemia in past in vitro studies varies with the temperature used to maintain the slices (< 30 min at 35-36°C and ≈ 60 min at 30°C), since metabolic demands of tissue during hypoglycemia are highly temperature dependent [6,41]. The reversible loss of fEPSP induced by 30 min of aglycemia at 35°C [36] becomes irreversible in our experiments (also at 35°C) by 60 min. Other studies using submerged slices demonstrate low glucose can induce decreased fEPSP slope at a variety of temperatures [10,36,45].…”

“…The observed decline in fEPSP amplitude following reductions in glucose concentrations to 2.5 mM or lower was gradual [20,36]. Clear cognitive sequelae appear to occur in the presence of low serum glucose after only minutes, suggesting that brain energy reserves (ie, glycogen) are very limited.…”

Context-dependent memory following recurrent hypoglycaemia in non-diabetic rats is mediated via glucocorticoid signalling in the dorsal hippocampus

“…Adolescent recurrent hypoglycaemia chronically reduces hypothalamic corticotrophin releasing hormone and GRs, but elevates both GRs and MRs in the hippocampus [14]. A similar regional contrast is seen with regard to cell death: glucose-sensing regions of the hypothalamus undergo apoptosis [15] and suppression [16], but the hippocampus adapts to hypoglycaemia, maintains synaptic transmission [17], increases glucose availability [8] and increases glutamatergic signalling during hypoglycaemia [18]. These changes may underlie altered cognitive performance: brain glucocorticoid signalling transduces the impact of recurrent hypoglycaemia on hypothalamic glucose-sensing and impaired awareness of hypoglycaemia [19], supporting this mechanism as a plausible candidate to mediate the neural impact of recurrent hypoglycaemia in the hippocampus.…”

Molecular and Physiological Responses to Juvenile Traumatic Brain Injury: Focus on Growth and Metabolism

“…The expression of these transporters shows dynamic age-related changes after brain injury. Increases in both GLUT1 and MCT1 protein expression have been shown following hypoglycemia [65,66] and hypoxia/ischemia [67,68,69,70,71]. More recently, our laboratory has shown an increased expression of endothelial MCT2 [72] and MCT1 with a trend toward decreased GLUT1 expression in injured P35 rats.…”