Homeostatic control of brain function - new approaches to understand epileptogenesis

Abstract

Neuronal excitability of the brain and ongoing homeostasis depend not only on intrinsic neuronal properties, but also on external environmental factors; together these determine the functionality of neuronal networks. Homeostatic factors become critically important during epileptogenesis, a process that involves complex disruption of self-regulatory mechanisms. Here we focus on the bioenergetic homeostatic network regulator adenosine, a purine nucleoside whose availability is largely regulated by astrocytes. Endogenous adenosine modulates complex network function through multiple mechanisms including adenosine receptor-mediated pathways, mitochondrial bioenergetics, and adenosine receptor-independent changes to the epigenome. Accumulating evidence from our laboratories shows that disruption of adenosine homeostasis plays a major role in epileptogenesis. Conversely, we have found that reconstruction of adenosine's homeostatic functions provides new hope for the prevention of epileptogenesis. We will discuss how adenosine-based therapeutic approaches may interfere with epileptogenesis on an epigenetic level, and how dietary interventions can be used to restore network homeostasis in the brain. We conclude that reconstruction of homeostatic functions in the brain offers a new conceptual advance for the treatment of neurological conditions which goes far beyond current target-centric treatment approaches.

Keywords: DNA methylation; adenosine; epileptogenesis; glial cells; homeostasis; ketogenic diet; mitochondrial bioenergetics and physiology; transmethylation pathway.

FIGURE 1

Epilepsy-associated alteration of astrocyte-based homeostatic functions. Summary of key pathophysiological alterations of astrocytes as found in animal models of epilepsy and/or in human epilepsy. For details, please refer to main text.

FIGURE 2

Adenosine tone regulates the transmethylation pathway. Pathways in blue reflect steady state pathways, whereas pathways in red show pathway shifts induced by alteration of adenosine homeostasis. Physiological baseline: DNA methylation of cytosine residues is mediated by the transmethylation pathway. S-adenosylmethionine (SAM) donates a methyl group, which is added to cytosine residues by DNMT. In the process SAM is converted to S-adenosylhomocysteine (SAH). SAH is further converted to adenosine (ADO) and homocysteine (HCY) by the enzyme S-adenosylhomocysteine hydrolase. ADO is phosphorylated to AMP by the enzyme adenosine kinase (ADK). HCY is converted to methionine and subsequently back to SAM. DNA methylation is dependent on the constant removal of the obligatory endproducts ADO and HCY. Phase I (epileptogenic trigger): we hypothesize that the injury and/or SE induced decrease of ADK and surge of ADK (Clark et al., 1997; Gouder et al., 2004; Pignataro et al., 2008) shifts the equilibrium constant of the transmethylation pathway to SAH. The increased SAH prevents SAM donation of a methyl group to DNA. Reduced DNA methylation permits the transcription of early epileptogenesis genes. Phase II (epileptogenic condition): increased ADK within reactive astrocytes reduces adenosine tone to pathologically low levels. Low adenosine tone shifts the biochemical pathway to favor SAM conversion to SAH; thereby, DNA methylation will be increased. Pathological hypermethylation of DNA is present in resected hippocampi of mTLE with hippocampal sclerosis patients (Kobow et al., 2009).