Convergence of Pre- and Postsynaptic Influences on Glucosensing Neurons in the Ventromedial Hypothalamic Nucleus

Abstract

Glucosensing neurons in the ventromedial hypothalamic nucleus (VMN) were studied using visually guided slicepatch recording techniques in brain slices from 14-to 21-day-old male Sprague-Dawley rats. Whole-cell current-clamp recordings were made as extracellular glucose levels were increased (from 2.5 to 5 or 10 mmol/l) or decreased (from 2.5 to 0.1 mmol/l). Using these physiological conditions to define glucosensing neurons, two subtypes of VMN glucosensing neurons were directly responsive to alterations in extracellular glucose levels. Another three subtypes were not directly glucose-sensing themselves, but rather were presynaptically modulated by changes in extracellular glucose. Of the VMN neurons, 14% were directly inhibited by decreases in extracellular glucose (glucose-excited [GE]), and 3% were directly excited by decreases in extracellular glucose (glucose-inhibited [GI]). An additional 14% were presynaptically excited by decreased glucose (PED neurons). The other two subtypes of glucosensing neurons were either presynaptically inhibited (PIR; 11%) or excited (PER; 8%) when extracellular glucose was raised to >2.5 mmol/l. GE neurons sensed decreased glucose via an ATP-sensitive K ؉ (K ATP ) channel. The inhibitory effect of increased glucose on PIR neurons appears to be mediated by a presynaptic ␥-aminobutyric acid-ergic glucosensing neuron that probably originates outside the VMN. Finally, all types of glucosensing neurons were both fewer in number and showed abnormal responses to glucose in a rodent model of diet-induced obesity and type 2 diabetes.

Involvement of neuropeptide Y in glucose sensing in the dorsal hypothalamus of streptozotocin diabetic rats – in vitro and in vivo studies of transmitter release

“…The PVN is known to contain GR neurons, while the ARC contains both GS [19] and GR [30] neurons. The ventral hypothalamus segment also incorporated the VMN, which contains both GR, and somewhat fewer, GS neurons [15]. In line with previous studies [26] increased basal NPY overflow was observed in both the dorsal and ventral hypothalamus as a result of treatment with STZ, and the increase was greater in the dorsal area.…”

“…Glucose sensing in the central nervous system (CNS) has been associated with the glucose sensing neurons [13]. Clear evidence of abnormalities in central glucose sensing and transport have been shown in Type I diabetes, involving a resetting of the normal homeostatic mechanisms [14], and more recently in diet-induced obesity [15].…”

ABCC8 and ABCC9: ABC transporters that regulate K+ channels

“…In the ventromedial hypothalamus (VMH), a majority of responding neurons increased their firing rate (glucose-responsive or glucose-stimulated), whereas in the lateral hypothalamus (LH), a majority reduced their activity (glucose-sensitive or glucose-inhibited). These results have been elegantly confirmed and extended by more recent studies, for example [142,145]. Several reports and experiments on K IR 6.2KO mice (98; see 28, 86, 125 for review) indicate that glucose-stimulated neurons in the VMH underlie the counterregulatory response to hypoglycemia, although Yang et al [155] have reported that glucose-inhibited neurons are involved.…”

“…The right panel illustrates three potential mechanisms whereby glucose metabolism is hypothesized to hyperpolarize glucose-inhibited neurons and decrease their firing rate. Song et al [145] have suggested metabolic activation of an inward chloride (Cl − ) flux would result in hyperpolarization as diagramed in the lower left side of the right panel. Following the astrocyte-neuron lactate shuttle model [33,76,115] and Lam et al [83], glucose metabolism in astrocytes leads to shuttling of lactate (Lac) into neurons via monocarboxylate transporters (MCTs), where it is converted to pyruvate (Pyr) and metabolized in mitochondria.…”

“…This would be consistent with the [Na + ] i and [K + ] i determinations of Silver and Erecińska [142] on glucose-inhibited neurons, and both insulin and long-chain acyl CoAs are reported to stimulate the sodium pump. (2) Song et al [145] proposed metabolic activation of a Cl − influx as the basis for hyperpolarization of glucose-inhibited (GI) neurons in the ventromedial nucleus. (3) The activation of K ATP channels by LC-CoA is a potential mechanism.…”