Elegantly, such a scheme could regulate the energy supplied to ne

Elegantly, such a scheme could regulate the energy supplied to neurons in response to their activity, since glutamate released by active neurons could promote lactate production in astrocytes

by stimulating glycolytic ATP generation to power astrocytic uptake of glutamate and its conversion to glutamine. CX-5461 manufacturer Neuronal activity does elevate lactate levels in the brain (Prichard et al., 1991), some studies (but not others) show that lactate can replace glucose as a power source for neurons (Schurr et al., 1988; Allen et al., 2005; Wyss et al., 2011), and lactate transporters are found in postsynaptic spines where most neuronal ATP is used (Bergersen et al., 2005). However, the extent to which astrocytes “feed” neurons, and even the direction of any lactate flux between the two cell types, remain controversial (Jolivet et al., 2010; Mangia et al., 2011). Consequently, a demonstration that

long-term potentiation and memory are disrupted by deletion of lactate transporters (Suzuki et al., 2011; Newman et al., 2011) might reflect a signaling role for lactate, rather than an energetic one. Indeed, one way in which lactate may provide synapses with energy is by being employed as a prostaglandin-modulating messenger to increase blood flow (Gordon et al., 2008; Attwell et al., 2010). Synaptic activity is far from constant and changes dramatically NLG919 solubility dmso on time scales from seconds to days. How then is ATP production by synaptic mitochondria regulated to match this demand? We will consider short-term regulation of energy supply in this section, and long-term regulation below. When ATP is consumed pre- and postsynaptically by the processes shown in Figure 1, the resulting increase of [ADP]/[ATP]

will, by the law of mass action, tend to increase ATP formation by oxidative phosphorylation (Chance and Williams, 1955). However, the rise of [Ca2+]i that occurs presynaptically to control transmitter release and postsynaptically at synapses expressing found NMDA receptors (or Ca2+-permeable AMPA receptors) provides another stimulus increasing ATP production rapidly in response to synaptic activity (Chouhan et al., 2012; see Gellerich et al. [2010] for a review and Mathiesen et al. [2011] for an opposing view). The rise of [Ca2+]i leads to a rise of mitochondrial [Ca2+]i, which activates mitochondrial dehydrogenases that promote citric acid cycle activity (Duchen, 1992). The rise of cytoplasmic [Ca2+]i also activates the mitochondrial aspartate-glutamate exchanger aralar (Gellerich et al., 2009), which raises [NADH] in mitochondria and thus supports H+ pumping out across the mitochondrial membrane and subsequent ATP synthesis. Antiapoptotic Bcl2 family proteins may also regulate ATP production by decreasing ion leak through the F1FO ATP synthase (Alavian et al., 2011). Activity-evoked entry of Ca2+ into synaptic mitochondria buffers the cytoplasmic [Ca2+]i rise occurring (Billups and Forsythe, 2002).

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