Mechanisms for maintaining extracellular glutamate levels in the anoxic turtle striatum

Abstract

The turtle Trachemys scripta is one of a limited group of vertebrates that can withstand hours to days without oxygen. One facet of anoxic survival is the turtle's ability to maintain basal extracellular glutamate levels, whereas in most vertebrates, anoxia triggers massive excitotoxic glutamate release. We investigated glutamate release and reuptake in the anoxic turtle and the effects of adenosine and ATP-sensitive potassium (K(ATP)) channels on glutamate homeostasis. Striatal extracellular glutamate was measured in anesthetized T. scripta by microdialysis in normoxia and over 2-h anoxia. Glutamate release is decreased by 44% in the early anoxic turtle; this anoxia-induced decrease in glutamate release was prevented when K(ATP) channels and adenosine receptors were blocked simultaneously but not when either mechanism was blocked individually. We hypothesize that the continued release and reuptake of glutamate during anoxia help maintain neuronal tone and aid in the recovery of a functional neuronal network after long periods of anoxia, whereas activation of adenosine and/or K(ATP) conserves energy by reducing glutamate release and lowering transport costs.

Activation of ATP-sensitive K+(KATP) channels by H2O2underlies glutamate-dependent inhibition of striatal dopamine release

“…Exogenous H 2 O 2 has been shown to lead to K ATPchannel opening in beta cells and subsequent inhibition of insulin release (36); however, a role for endogenous H 2 O 2 in K ATP -channel regulation has not been reported previously. The normally closed state of K ATP channels in the CNS and their known activation by deprivation of oxygen and͞or glucose have suggested that a primary function is to provide neuroprotection during ischemia or other brain injury (8,17,27,29,31,(75)(76)(77). However, these channels also have significant roles in normal physiology, including maintenance of glucose homeostasis by glucose-sensing cells of the hypothalamus (32-34) and regulation of excitability in metabolically sensitive cells of the vagal and respiratory centers (35,36).…”

“…For example, in DA neurons of the substantia nigra pars compacta, K ATP channels do not contribute to resting membrane properties, although membrane hyperpolarization occurs when these channels are activated by selective openers or decreased levels of oxygen and͞or glucose (15)(16)(17)(18)(19)(20). Consistent with these data, activation of K ATP channels by specific openers or by metabolic inhibition decreases the release of several neurotransmitters, including DA (21,22), ␥-aminobutyric acid (GABA) (15,(23)(24)(25)(26), and glutamate (27)(28)(29)(30)(31). Together, these data have suggested that brain K ATP channels may provide neuroprotection during metabolic stress.…”

Controlling anoxic tolerance in adult Drosophila via the cGMP–PKG pathway

“…Facultative anaerobes are evolutionarily adapted to withstand long periods without oxygen; anoxia survival tolerance of at least several hours has been established in the fruit fly D. melanogaster (Wingrove and O'Farrell, 1999;Haddad, 2006) while some turtles can withstand anoxia for days to months (Ultsch, 2006). These anoxia-tolerant organisms, in contrast to mammalian systems, enter a state of deep reversible hypometabolism, thereby losing neural function but maintaining a balance between energy requirements and supply by suppressing energy-demanding functions, including the release of excitatory neurotransmitters (Milton et al, 2002;Milton and Lutz, 2005) and ion flux (Sick et al, 1982;Perez-Pinzon et al, 1992;Bickler et al, 2000), which together suppress electrical activity (Fernandes et al, 1997;Gu and Haddad, 1999). Anoxia tolerance then permits survival of extended anoxia without neuronal deficit (Haddad, 2006;Kesaraju et al, 2009).…”

“…By contrast, an up-regulation of the PKG pathway increases cell survival; it is not yet known if this occurs by a more rapid suppression of function, such as what is shown in turtles (Milton et al, 2002). Under anoxic stress, anoxia-tolerant animals such as turtles suppress metabolic requirements and enter a coma-like state.…”

Gene transcription of neuroglobin is upregulated by hypoxia and anoxia in the brain of the anoxia-tolerant turtle Trachemys scripta

“…By preventing an energy deficit, the turtle brain avoids the catastrophic drop in ATP levels which, in mammalian neurons, results in the breakdown of cellular ion homeostasis, release of excitatory neurotransmitters, and excitotoxic cellular death [1]. To decrease neuronal energy requirements, Trachemys decreases membrane ion permeability (''channel arrest''), inhibits the release of excitatory neurotransmitters such as dopamine [10] and glutamate [11], increases the release of inhibitory compounds including adenosine [12] and GABA [13], and decreases electrical activity [14]. In terms of molecular changes, organ-level alterations of MAP kinases, ERK, and JNK have been reported [15], while work in our lab has shown increased expression of heat shock proteins [16] and the downregulation of Kv channel transcription [17]; alterations in many of these molecular factors have been linked to hypoxic/ischemic survival in the mammalian CNS.…”