Connexin-43 Gap Junctions Are Responsible for the Hypothalamic Tanycyte-Coupled Network

Abstract

Tanycytes are hypothalamic radial glia-like cells that form the basal wall of the third ventricle (3V) where they sense glucose and modulate neighboring neuronal activity to control feeding behavior. This role requires the coupling of hypothalamic cells since transient decreased hypothalamic Cx43 expression inhibits the increase of brain glucose-induced insulin secretion. Tanycytes have been postulated as possible hypothalamic neuronal precursors due to their privileged position in the hypothalamus that allows them to detect mitogenic signals and because they share the markers and characteristics of neuronal precursors located in other neurogenic niches, including the formation of coupled networks through connexins. Using wild-type (WT), Cx30−/– and Cx30−/–, Cx43fl/fl:glial fibrillary acidic protein (GFAP)-Cre (double knockout, dKO) mouse lines, we demonstrated that tanycytes are highly coupled to each other and also give rise to a panglial network specifically through Cx43. Using the human GFAP (hGFAP)-enhanced green fluorescent protein (EGFP) transgenic mouse line, we provided evidence that the main parenchymal-coupled cells were astrocytes. In addition, electrophysiological parameters, such as membrane resistance, were altered when Cx43 was genetically absent or pharmacologically inhibited. Finally, in the dKO mouse line, we detected a significant decrease in the number of hypothalamic proliferative parenchymal cells. Our results demonstrate the importance of Cx43 in tanycyte homotypic and panglial coupling and show that Cx43 function influences the proliferative potential of hypothalamic cells.

Tanycytes: A rich morphological history to underpin future molecular and physiological investigations

“…24 Szilvásy-Szabó et al 79 have recently reported that connexin 43 immunoreactivity is strong in α-tanycytes and weak in β-tanycytes; they also described gap junctions between α-tanycyte terminals and demonstrated coupling by loading individual tanycytes with Lucifer yellow. 79,80 More recently, Recabal et al 81 have also demonstrated that tanycytes are highly coupled to each other and to astrocytes and oligodendrocytes, giving rise to a panglial network through Cx43. However, the function of tanycyte homotypic and panglial coupling is still unknown.…”

“…However, the function of tanycyte homotypic and panglial coupling is still unknown. Notably, hypothalamic cell proliferation was altered when connexin 43 expression was suppressed, 81 suggesting that Cx43 function may influence the proliferative potential of hypothalamic cells and adult neurogenesis.…”

Tanycyte Gene Expression Dynamics in the Regulation of Energy Homeostasis

“…In particular, α tanycytes making contact with BBB capillaries and/or neurons express GLAST ( Slc1a3 ) (17, 43), MCT1 ( Slc16a1 ) and MCT4 ( Slc16a4 ) (29) involved in the recapture of glutamate and lactate transport, respectively, necessary for the modulation of neuronal activity. They also express connexin 43 ( Gja1 ), a component of gap junction which allow intercellular communications between adjacent cells (44–46). α tanycytes also express Fgf18 (40) and Prss56 (47), which have been associated to their stem/progenitor cell function.…”

“…Central control of energy balance requires the monitoring of many circulating signals–including both circulating metabolites such as glucose, free fatty acids and amino acids, and secreted hormones such as ghrelin, leptin and insulin–that provide information about the nutritional status and body energy stores. Many studies have described tanycytes as metabolic sensors able to detect glucose (13, 14, 44, 46), amino acids (15), or leptin (11). Tanycytes (mainly α tanycytes and in a lesser extend β tanycytes) have mainly been shown to be able to detect changes in glucose levels in the CSF and release paracrine factors (e.g., ATP), that activate neighboring tanycytes (13) but could also potentially activate neighboring hypothalamic neurons (59, 60).…”

“…As other glial cells, calcium signaling is crucial in tanycytes. Induced by different stimuli including glucose (13), amino acids (15), ATP (13), non-metabolizable glucose analogs (14), TRH (28), the increase in intracellular calcium in tanycytes is able to propagate as calcium waves from one tanycyte to another through gap junctions (13, 44). These calcium waves may synchronize gene expression in tanycytes and/or tanycyte subgroups.…”