Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain.

The ketogenic diet (KD) has been successfully used for a century for treating refractory epilepsy and is currently seen as one of the few viable approaches to the treatment of a plethora of metabolic and neurodegenerative diseases. Empirical evidence notwithstanding, there is still no universal understanding of KD mechanism(s). An important fact is that the brain is capable of using ketone bodies for fuel. Another critical point is that glucose's functions span beyond its role as an energy substrate, and in most of these functions, glucose is irreplaceable. By acting as a supplementary fuel, ketone bodies may free up glucose for its other crucial and exclusive function. We propose that this glucose-sparing effect of ketone bodies may underlie the effectiveness of KD in epilepsy and major neurodegenerative diseases, which are all characterized by brain glucose hypometabolism.

Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis.

The energy demands of the brain are exceptionally high compared with any other organ of the body. A complex control system maintains brain energy homeostasis, mobilizing appropriate energy substrates to satisfy the energy requirements. It is a common belief that many fundamental neuronal properties, including those governing excitability, are dependent on the energy supply. However, surprisingly little is known about how the specific factors underlying neuronal activity are affected by energy status. Most of these parameters have been studied in acute brain slices, in which the homeostatic system is absent and neurons in the artificial extracellular milieu are arbitrarily supplied with energy substrates. In this paper, we discuss the relationships between availability of energy substrates and neuronal excitability, and suggest that for in vitro studies, it is crucial to optimize the composition of the energy pool in the extracellular milieu.

GABA action in immature neocortical neurons directly depends on the availability of ketone bodies.

In the early postnatal period, energy metabolism in the suckling rodent brain relies to a large extent on metabolic pathways alternate to glucose such as the utilization of ketone bodies (KBs). However, how KBs affect neuronal excitability is not known. Using recordings of single NMDA and GABA-activated channels in neocortical pyramidal cells we studied the effects of KBs on the resting membrane potential (E(m)) and reversal potential of GABA-induced anionic currents (E(GABA)), respectively. We show that during postnatal development (P3-P19) if neocortical brain slices are adequately supplied with KBs, E(m) and E(GABA) are both maintained at negative levels of about -83 and -80 mV, respectively. Conversely, a KB deficiency causes a significant depolarization of both E(m) (>5 mV) and E(GABA) (>15 mV). The KB-mediated shift in E(GABA) is largely determined by the interaction of the NKCC1 cotransporter and Cl(-)/HCO3 transporter(s). Therefore, by inducing a hyperpolarizing shift in E(m) and modulating GABA signaling mode, KBs can efficiently control the excitability of neonatal cortical neurons.