Regulation of extracellular glutamate levels in the long-term anoxic turtle striatum: coordinated activity of glutamate transporters, adenosine, KATP+ channels and GABA

Abstract

Early in anoxia the mammalian brain experiences an uncontrolled release of glutamate, which combined with the failure of glutamate reuptake mechanisms, leads to massive neurotoxic increases in extracellular glutamate. By contrast, the anoxia tolerant turtle (Trachemys scripta) shows no increase in extracellular glutamate levels over many hours of anoxia. During the first hours of anoxia extracellular glutamate levels are maintained by a reduction in glutamate release (mainly due to the inhibition of neuronal vesicular glutamate release), combined with continued uptake by still active glutamate transporters. The early down-regulation in glutamate release is modulated by adenosine receptors and K (ATP) (+) channels, but is not affected by GABA(A )receptors. During long-term anoxia there is a further reduction in the rate of glutamate release, reaching 30% of normoxic control values at 5 h of anoxia. Adenosine and GABA(A) receptors but not K (ATP) (+) channels regulate this reduction in glutamate release. We conclude that the reduction in glutamate release during progressive anoxia is a dynamic process requiring continuous but changing synergistic activity of K (ATP) (+) channels, adenosine and GABA(A) receptors. The fact that there is a still active glutamate release and uptake in prolonged anoxia suggests that extracellular glutamate has a vital function in the deeply hypometabolic brain.

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

“…AMPA receptor currents, meanwhile, are also reduced by activation of mitochondrial ATP-dependent K + channels (Zivkovic and Buck, 2010), which in turn also reduce glutamate and dopamine release in early anoxia (Milton and Lutz, 2005;Milton et al, 2002). In longer anoxic exposures, glutamate release is suppressed by adenosine and GABA (Thompson et al, 2007). Adenosine in turn affects channel arrest (Pék and Lutz, 1997;Pérez-Pinzón et al, 1993), dopamine release (Milton and Lutz, 2005;Milton et al, 2002), NMDAR currents (Buck and Bickler, 1998) and cerebral blood flow (Hylland et al, 1994).…”

“…Energy demanding processes are greatly suppressed; in the turtle brain these include decreases in excitatory neurotransmitter release (Milton and Lutz, 1998;Milton et al, 2002;Thompson et al, 2007), and increased neural inhibition (Lutz and Manuel, 1999;Nilsson and Lutz, 1991;Nilsson and Lutz, 1992). Decreased ion permeability (channel arrest), and the suppression of action potentials (spike arrest) also contribute to significant energy savings.…”

Anoxia-mediated calcium release through the mitochondrial permeability transition pore silences NMDA receptor currents in turtle neurons

“…In addition to maintaining extracellular [glutamate] at basal levels through 5 h of anoxia (Thompson et al, 2007), turtle neurons regulate NMDAR activity through a reduction in channel open time; open probability is reduced by 65% after 60 min of anoxia ) and whole-cell NMDAR currents are reduced by 45-65% after 40 min of anoxia (Pamenter et al, 2008b;Shin and Buck, 2003;Bickler et al, 2000). These changes occur in a calcium-dependent manner: [Ca 2+ ] i levels increase by 35% following the onset of anoxia (Bickler et al, 2000) and inclusion of the Ca 2+ chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid] in the pipette solution of electrodes during wholecell patch clamp experiments abolished the anoxia-mediated reduction in NMDAR currents (Pamenter et al, 2008b).…”

Cellular Basis for Learning Impairment in Fragile X Syndrome

“…As with some of the other models discussed in this review, one mechanism to extend anoxic survival is entrance into a state of deep reversible hypo-metabolism; energy demand is reduced to meet the energy supplied by anaerobic glycolysis. Energy demanding processes are greatly suppressed; in the turtle brain these include decreases in excitatory neurotransmitter release (Milton and Lutz, 1998; Milton et al, 2002;Thompson et al, 2007), and increased neural inhibition (Lutz and Manuel, 1999; Nilsson and Lutz, 1991; Nilsson and Lutz, 1992). Decreased ion permeability (channel arrest), and the suppression of action potentials (spike arrest) also contribute to significant energy savings.…”

“…AMPA receptor currents, meanwhile, are also reduced by activation of mitochondrial ATP-dependent K + channels (Zivkovic and Buck, 2010), which in turn also reduce glutamate and dopamine release in early anoxia (Milton and Lutz, 2005; Milton et al, 2002). In longer anoxic exposures, glutamate release is suppressed by adenosine and GABA (Thompson et al, 2007). Adenosine in turn affects channel arrest (Pék and Lutz, 1997;Pérez-Pinzón et al, 1993), dopamine release (Milton and Lutz, 2005; Milton et al, 2002), NMDAR currents (Buck andBickler, 1998) and cerebral blood flow (Hylland et al, 1994).…”