MCT Expression and Lactate Influx/Efflux in Tanycytes Involved in Glia-Neuron Metabolic Interaction

Metabolic interaction via lactate between glial cells and neurons has been proposed as one of the mechanisms involved in hypothalamic glucosensing. We have postulated that hypothalamic glial cells, also known as tanycytes, produce lactate by glycolytic metabolism of glucose. Transfer of lactate to neighboring neurons stimulates ATP synthesis and thus contributes to their activation. Because destruction of third ventricle (III-V) tanycytes is sufficient to alter blood glucose levels and food intake in rats, it is hypothesized that tanycytes are involved in the hypothalamic glucose sensing mechanism. Here, we demonstrate the presence and function of monocarboxylate transporters (MCTs) in tanycytes. Specifically, MCT1 and MCT4 expression as well as their distribution were analyzed in Sprague Dawley rat brain, and we demonstrate that both transporters are expressed in tanycytes. Using primary tanycyte cultures, kinetic analyses and sensitivity to inhibitors were undertaken to confirm that MCT1 and MCT4 were functional for lactate influx. Additionally, physiological concentrations of glucose induced lactate efflux in cultured tanycytes, which was inhibited by classical MCT inhibitors. Because the expression of both MCT1 and MCT4 has been linked to lactate efflux, we propose that tanycytes participate in glucose sensing based on a metabolic interaction with neurons of the arcuate nucleus, which are stimulated by lactate released from MCT1 and MCT4-expressing tanycytes

Modulation of NMDA Receptor Channels by Intracellular Calcium

In the mammalian central nervous system (CNS) excitatory synaptic transmission is mediated by glutamate which co-activates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptor (AMPAR) channels, co-localized in the postsynaptic membrane. Fast synaptic currents are mediated by AMPAR channels whereas NMDAR channels generate slower, longer lasting currents (Forsythe & Westbrook, 1988; Bekkers & Stevens, 1989; Stern et al., 1992; Spruston et al., 1995). NMDAR channels are highly permeable for Ca2+ (MacDermott et al., 1986; Mayer & Westbrook, 1987; Ascher & Nowak, 1988) and contribute to the synaptically evoked elevation of Ca2+ in dendritic spines (Müller & Connor, 1991; Perkel et al., 1993; Malinow et al., 1994). Native NMDAR are heteromeric channels composed of NR1 and one or more of the four NR2 subunits belonging to the NMDAR family of ionotropic glutamate receptors (Hollmann & Heinemann, 1994). Each of the subunit imparts specific functional property to the channel providing a wide spectrum for the regulation of the NMDAR channel function. The NMDAR is a subject to modulation by a number of extracellular and intracellular agents including Mg2+, Zn2+, glycine, polyamines, protons, reducing agents, protein kinases and Ca2