The preceding sections have explained how synapses can reduce their energy use and where they get their energy from. We turn now to changes of synaptic energy use in development, synaptic plasticity, and sleep. As brains develop they initially increase their energy use above the adult value, but beyond adolescence aging is associated with a decrease of energy use (Gleason et al., 1989; Leenders et al., 1990). These changes correlate with an increase in the thickness

of the cortex as many synaptic connections are made, followed by cortical thinning as connections are pruned and the brain reaches its mature state (reviewed by Harris et al., 2011). The high energy use during development reflects not only the larger number of energy-consuming synapses but also the ATP used to synthesize cellular components. NVP-AUY922 mw On top of changes in the number of synapses, changes in the energy used per synapse occur during development, as a result of the recruitment of AMPA receptors to excitatory synapses that initially contain mainly NMDA receptors (Hall and Ghosh, 2008), and changes in the NMDA receptor subunits present which shorten the synaptic current and thus reduce ATP consumption (Hestrin, 1992b). Furthermore, GABAergic synapses may use more energy early in development, when the accumulation of Cl− by NKCC1

transporters results in GABAA receptors being excitatory, compared with the mature brain, when the [Cl−] gradient is set by KCC2 transporters exporting Cl− and GABAA receptors AZD5363 molecular weight are inhibitory (Ben-Ari, 2002). Early in development restoring the [Cl−] gradient, after synaptic transmission DNA ligase causes a depolarizing efflux of Cl−, will require Na+ entry on NKCC1 (and hence subsequent ATP use on the Na+ pump), unlike in the mature brain where reversing a hyperpolarizing Cl− influx

is performed by KCC2 and uses little energy (Howarth et al., 2010). As in the developing brain, synaptic strength in the mature brain can be increased or decreased by plasticity processes, and this will alter energy expenditure. For example, NMDA receptor-dependent long-term potentiation can double the strength of synapses by inserting more AMPA receptors into the postsynaptic membrane, doubling their postsynaptic energy consumption and requiring an increased ATP supply to the potentiated synapses (Wieraszko, 1982). Accordingly, a negative feedback mechanism mediated by AMP-dependent protein kinase prevents the maintenance of synapse potentiation when cellular energy supplies are challenged (Potter et al., 2010). In addition, long-term potentiation and memory are disrupted by deletion of lactate transporters (Suzuki et al., 2011; Newman et al., 2011), but it is unclear whether this reflects an energetic or a signaling function of lactate (see above).