Regulation of neuronal bioenergy homeostasis by glutamate

Abstract

Bioenergy homeostasis is crucial in maintaining normal cell function and survival and it is thus important to understand cellular mechanisms underlying its regulation. Neurons use a large amount of ATP to maintain membrane potential and synaptic communication, making the brain the most energy consuming organ in the body. Glutamate mediates a large majority of synaptic transmission which is responsible for the expression of neural plasticity and higher brain functions. Most of the energy cost is attributable to the glutamatergic system; under pathological conditions such as stroke and brain ischemia, neural energy depletion is accompanied by a massive release of glutamate. However, the specific cellular processes implicated in glutamate-dependent bioenergy dynamics are not well understood. We find that glutamate induces a rapid and dramatic reduction of ATP levels in neurons, through reduced ATP genesis and elevated consumption. ATP reduction depends on NMDA receptor activity, but is not a result of neuronal firing, gap junction-mediated leaking or intracellular signaling. Similar changes in ATP levels are also induced by synaptic glutamate accumulation following suppression of glutamate transporter activity. Furthermore, the glutamate-induced ATP down-regulation is blocked by the sodium pump inhibitor ouabain, suggesting the sodium pump as the primary energy consumer during glutamate stimulation. These data suggest the important role of glutamate in the control of cellular ATP homeostasis.

A Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau

“…Our results are consistent with the previous report that spine damage is a preceding neuropathological process contributing to neuronal injury after stroke, possibly due to the high sensitivity of synaptic activity to alterations in energy supply ( Khatri and Man 2013 ). For example, results from magnetic resonance spectroscopy related the changes in neuroenergetics revealed that more energy were required for functional activation to neurotransmitter cycling at the level of the synapse ( Waldvogel et al 2000 ; Foo et al 2012 ). And the structural and functional integrity of synaptic transmission profoundly depends on a superior oxygen and glucose supply ( Acker and Acker 2004 ).…”

Synaptic Activity and Bioenergy Homeostasis: Implications in Brain Trauma and Neurodegenerative Diseases

“…However, exposure of neurons to glutamate results in a reduction in cellular ATP levels (20) and glucose uptake in neurons (42), indicating distinct signaling and cellular responses to synaptic vs. non-synaptic glutamate receptor activation.…”

Central Glutamatergic-Purinergic System Importance in Brain/Neural Plasticity

“…Additional physical exercise increases the neural plasticity and the activity of neural tracts. It was well confirmed that glutamate is a main excitatory neurotransmitter, which intermediates a substantial most of synaptic transmission and neural plasticity, as well as higher brain functions [20]. Various current investigations demonstrate that physical training likewise features an critical importance in angiogenesis and practical restoration following cerebral stroke [21].…”