Glucose deprivation slowly depressed fEPSP amplitude (T1/2 [time to half amplitude] = 31.1 ± 3.3 min; Figure 6A, open circles) (Fowler, 1993; Schurr et al., 1988). In 2-OH, glucose deprivation caused a significantly faster decline of fEPSPs (T1/2 = 15.0 ± 1.4 min, p < 0.001; Figure 6A, filled circles), with poorer recovery compared to glucose deprivation alone. fEPSP traces from corresponding time points are shown in Figure 6B. The depression of fEPSP by inhibiting sAC with 2-OH was rescued by the addition of exogenous lactate (5 mM) (T1/2 = 23.4 ± 1.9 min; + 2-OH: T1/2 = 22.1 ± 2.3 min, p > 0.05; Figure 6C). fEPSP traces from corresponding time points are

shown in Figure 6D. selleck chemicals These data suggest that aglycemia stimulates the sAC-dependent breakdown Doxorubicin datasheet of glycogen in astrocytes, leading to the generation and release of lactate to provide an energy substrate for neurons to maintain synaptic function. Here we report a mechanism in brain metabolic coupling in which astrocytes respond to an increase in [K+]ext or aglycemia by the activation

of HCO3−-sensitive sAC, an enzyme that is abundantly expressed in these cells within the brain. sAC activation leads to an increase in intracellular cAMP, which, in turn, triggers glycogen breakdown within astrocytes and the subsequent generation and release of lactate so that neurons are provided with additional energy substrates (see Figure 7 diagram). Our data show that this mechanism is recruited to help meet energy demand and maintain synaptic operation during moderate K+ challenges and during drastic reduction in levels of glucose, the brain’s most important fuel. With respect to K+ handling, our data show that the ability of astrocytes to respond to small changes in [K+]ext goes beyond the simple maintenance of ionic PAK6 homeostasis to which astrocytes are prescribed and instead reflects a broader functional significance in the coordination of energy utilization in the brain. K+-mediated HCO3− entry and sAC activation represent an elegant solution of detecting

the needs of neurons by virtue of the fact that action potentials and synaptic potentials require new fuel substrates to supply energy production required for Na+/K+ ATPase activity (Alle et al., 2009; Attwell and Laughlin, 2001). Elevation in intracellular free [Ca2+] in astrocytes is unlikely to have a role in K+-triggered metabolic coupling because the EC50 of calcium for sAC activation is 750 μM (Litvin et al., 2003), well above normal elevations in [Ca2+]i used for cell signaling. We did not detect calcium signals in astrocytes when 10 mM K+ was bath applied (Figure S5). In addition, the threshold for [K+]ext to evoke an elevation in [Ca2+]i in astrocytes is approximately 25 mM (Duffy and MacVicar, 1994), much higher than the 5–10 mM used here.