Local brain environment changes associated with epileptogenesis

Abstract

Plastic change of the neuronal system has traditionally been assumed to be governed primarily by the long-term potentiation/depression mechanisms of synaptic transmission. However, a rather simple shift in the ambient ion, transmitter and metabolite concentrations could have a pivotal role in generating plasticity upon the physiological process of learning and memory. Local brain environment and metabolic changes could also be the cause and consequences of the pathogenesis leading to epilepsy. Governing of the local brain environment is the primal function of astrocytes. The metabolic state of the entire brain is strongly linked to the activity of the lateral hypothalamus. In this study, plastic change of astrocyte reactions in the lateral hypothalamus was examined using epileptogenesis as an extreme form of plasticity. Fluorescent sensors for calcium or pH expressed in astrocytes were examined for up to one week by in vivo fibre photometry in freely moving transgenic male mice. Optical fluctuations on a timescale of seconds is difficult to assess because these signals are heavily influenced by local brain blood volume changes and pH changes. Using a newly devised method for the analysis of the optical signals, changes in Ca2+ and pH in astrocytes and changes in local brain blood volume associated with hippocampal-stimulated epileptic seizures were extracted. Following a transient alkaline shift in the astrocyte triggered by neuronal hyperactivity, a prominent acidic shift appeared in response to intensified seizure which developed with kindling. The acidic shift was unexpected as transient increase in local brain blood volume was observed in response to intensified seizures, which should lead to efficient extrusion of the acidic CO2. The acidic shift could be a result of glutamate transporter activity and/or due to the increased metabolic load of astrocytes leading to increased CO2 and lactate production. This acidic shift may trigger additional gliotransmitter release from astrocytes leading to the exacerbation of epilepsy. As all cellular enzymic reactions are influenced by Ca2+ and pH, changes in these parameters could also have an impact on the neuronal circuit activity. Thus, controlling the astrocyte pH and/or Ca2+ could be a new therapeutic target for treatment of epilepsy or prevention of undesired plasticity associated with epileptogenesis.

Keywords: SUDEP; astrocyte; epilepsy; fibre photometry; hypothalamus.