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The ability of a ketogenic diet to treat seizures and render a neuronal network more resistant to strong electrical activity has been observed for a century in clinics and for decades in research laboratories. Alongside ongoing efforts to understand how this therapy works to stop seizures, metabolic health is increasingly appreciated as critical buffer to resisting and recovering from acute and chronic disease. Accordingly, links between metabolism and health, and the broader emerging impact of the ketogenic diet in improving diverse metabolic, immunological and neurological conditions, have served to intensify the search for its key and/or common mechanisms. Here we review diverse evidence for increased levels of NAD + , and thus an altered ratio of NAD + /NADH, during metabolic therapy with a ketogenic diet. We propose this as a potential unifying mechanism, and highlight some of the evidence linking altered NAD + /NADH with reduced seizures and with a range of short and long-term changes associated with the beneficial effects of a ketogenic diet. An increase in NAD + /NADH is consistent with multiple lines of evidence and hypotheses, and therefore we suggest that increased NAD + may be a common mechanism underlying beneficial effects of ketogenic diet therapy., (Copyright © 2020. Published by Elsevier B.V.)

ATP and adenosine are purines that play dual roles in cell metabolism and neuronal signaling. Acting at the A(1) receptor (A(1)R) subtype, adenosine acts directly on neurons to inhibit excitability and is a powerful endogenous neuroprotective and anticonvulsant molecule. Previous research showed an increase in ATP and other cell energy parameters when an animal is administered a ketogenic diet, an established metabolic therapy to reduce epileptic seizures, but the relationship among purines, neuronal excitability and the ketogenic diet was unclear. Recent work in vivo and in vitro tested the specific hypothesis that adenosine acting at A(1)Rs is a key mechanism underlying the success of ketogenic diet therapy and yielded direct evidence linking A(1)Rs to the antiepileptic effects of a ketogenic diet. Specifically, an in vitro mimic of a ketogenic diet revealed an A(1)R-dependent metabolic autocrine hyperpolarization of hippocampal neurons. In parallel, applying the ketogenic diet in vivo to transgenic mouse models with spontaneous electrographic seizures revealed that intact A(1)Rs are necessary for the seizure-suppressing effects of the diet. This is the first direct in vivo evidence linking A(1)Rs to the antiepileptic effects of a ketogenic diet. Other predictions of the relationship between purines and the ketogenic diet are discussed. Taken together, recent research on the role of purines may offer new opportunities for metabolic therapy and insight into its underlying mechanisms., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Metabolic perturbations that decrease or limit blood glucose-such as fasting or adhering to a ketogenic diet-reduce epileptic seizures significantly. To date, the critical links between altered metabolism and decreased neuronal activity remain unknown. More generally, metabolic changes accompany numerous CNS disorders, and the purines ATP and its core molecule adenosine are poised to translate cell energy into altered neuronal activity. Here we show that nonpathological changes in metabolism induce a purinergic autoregulation of hippocampal CA3 pyramidal neuron excitability. During conditions of sufficient intracellular ATP, reducing extracellular glucose induces pannexin-1 hemichannel-mediated ATP release directly from CA3 neurons. This extracellular ATP is dephosphorylated to adenosine, activates neuronal adenosine A(1) receptors, and, unexpectedly, hyperpolarizes neuronal membrane potential via ATP-sensitive K(+) channels. Together, these data delineate an autocrine regulation of neuronal excitability via ATP and adenosine in a seizure-prone subregion of the hippocampus and offer new mechanistic insight into the relationship between decreased glucose and increased seizure threshold. By establishing neuronal ATP release via pannexin hemichannels, and hippocampal adenosine A(1) receptors coupled to ATP-sensitive K(+) channels, we reveal detailed information regarding the relationship between metabolism and neuronal activity and new strategies for adenosine-based therapies in the CNS.

Marijuana is a widely used drug that impairs memory through interaction between its psychoactive constituent, Delta-9-tetrahydrocannabinol (Delta(9)-THC), and CB(1) receptors (CB1Rs) in the hippocampus. CB1Rs are located on Schaffer collateral (Sc) axon terminals in the hippocampus, where they inhibit glutamate release onto CA1 pyramidal neurons. This action is shared by adenosine A(1) receptors (A1Rs), which are also located on Sc terminals. Furthermore, A1Rs are tonically activated by endogenous adenosine (eADO), leading to suppressed glutamate release under basal conditions. Colocalization of A1Rs and CB1Rs, and their coupling to shared components of signal transduction, suggest that these receptors may interact. We examined the roles of A1Rs and eADO in regulating CB1R inhibition of glutamatergic synaptic transmission in the rodent hippocampus. We found that A1R activation by basal or experimentally increased levels of eADO reduced or eliminated CB1R inhibition of glutamate release, and that blockade of A1Rs with caffeine or other antagonists reversed this effect. The CB1R-A1R interaction was observed with the agonists WIN55,212-2 and Delta(9)-THC and during endocannabinoid-mediated depolarization-induced suppression of excitation. A1R control of CB1Rs was stronger in the C57BL/6J mouse hippocampus, in which eADO levels were higher than in Sprague Dawley rats, and the eADO modulation of CB1R effects was absent in A1R knock-out mice. Since eADO levels and A1R activation are regulated by homeostatic, metabolic, and pathological factors, these data identify a mechanism in which CB1R function can be controlled by the brain adenosine system. Additionally, our data imply that caffeine may potentiate the effects of marijuana on hippocampal function.

In addition to affecting respiration and vascular tone, deviations from normal CO(2) alter pH, consciousness, and seizure propensity. Outside the brainstem, however, the mechanisms by which CO(2) levels modify neuronal function are unknown. In the hippocampal slice preparation, increasing CO(2), and thus decreasing pH, increased the extracellular concentration of the endogenous neuromodulator adenosine and inhibited excitatory synaptic transmission. These effects involve adenosine A(1) and ATP receptors and depend on decreased extracellular pH. In contrast, decreasing CO(2) levels reduced extracellular adenosine concentration and increased neuronal excitability via adenosine A(1) receptors, ATP receptors, and ecto-ATPase. Based on these studies, we propose that CO(2)-induced changes in neuronal function arise from a pH-dependent modulation of adenosine and ATP levels. These findings demonstrate a mechanism for the bidirectional effects of CO(2) on neuronal excitability in the forebrain.

The profile of activity across rat somatosensory cortex on stimulation of a single whisker was examined using both intrinsic signal imaging and electrophysiological recording. In the same animals, under sodium pentobarbital anesthesia, the intrinsic signal response to a 5-Hz stimulation of whisker C2 was recorded through a thinned skull. Subsequently, the thinned skull was removed, and individual cortical neurons were recorded at multiple locations and in all cortical layers in response to the same whisker stimulation paradigm. The amplitude of the evoked response obtained with both techniques was quantified across the cortical surface with respect to distance (1.6 mm) from the optically determined peak of activity. Overall, this analysis shows a significant correlation between the two techniques in terms of the profile of evoked activity across the cortical surface. Furthermore, this data set affords a detailed and quantitative comparison between the two activity-dependent techniques-one measuring an intrinsic decrease in light reflectance based largely on metabolic changes and one measuring neuronal firing patterns. Studies such as this, comparing directly between imaging and detailed electrophysiology, may influence the interpretation of the extent of the activated area as assessed with in vivo functional imaging techniques.