GLION · Investigating glial glycogen utilization for ion homeostasis in the brain and its relevance to epileptogenesis: electrophysiology and pharmacology in awake behaving mice
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-03-01 → 2018-02-28
- EU contribution
- €212,195
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Investigating glial glycogen utilization for ion homeostasis in the brain and its relevance to epileptogenesis: electrophysiology and pharmacology in awake behaving mice
The brain is one of the most energetically expensive organs in the body and energetic constraints limit brain information processing. Utilization of cerebral glycogen (polysaccharide of glucose, the sole form of glucose storage in the brain) within the glycolytic pathway has recently be shown to be critical for basic as well as higher brain functions, including neuronal excitability, sleep-wake cycle and cognitive abilities such as learning and memory. However, the exact reasons for why glycogenolysis and glycolysis are so essential to brain function remain unknown. The identification of the mechanisms underlying functional metabolism in the brain holds great potential to understand the relevance of energetic requirements to both physiological and pathological conditions. Indeed, impairments in brain metabolism often precede aberrant neuronal excitability and cognitive decline, which together represent significant social burdens and, as such, demand for effective therapeutic interventions. The overall objective of the present project is to increase our comprehension about the role of glycogen in neuronal activity, from basic cellular processes to the overall function of the organ. In particular, glycogen in the brain is confined to glial astrocytes and is implicated in the maintenance of homeostasis through the control of the levels of neuroactive compounds. Among these, potassium is a key regulator of neuronal excitability and involvement of glycogenolysis in potassium buffering is an established function for brain astrocytes. Furthermore, astrocytic glycogen is implicated in neurotransmitter homeostasis, both excitatory glutamate and inhibitory GABA through specific metabolic pathways. The conclusions of the action are supportive of the importance of glycogen and glycolysis in governing local as well as global brain activity in response to sensory stimulation, and in particular during conditions of increased noradrenergic tone. The latter finding indicates that increased glycolytic metabolism rises during a reorienting behavioral response, which is known to be associated with memory formation.
Data: CORDIS, © European Union
Project objective
We do not yet fully understand the cellular basis of brain energy metabolism. The high energy consumption of mammalian brain sets information processing under critical metabolic constraints. Energy efficiency in brain signaling is supported by functional and metabolic interactions between neuronal and astrocytic cells. Specifically, during neuronal activity astrocytes rapidly take up neuronally-released compounds from the extracellular space, including potassium (K+) and transmitter molecules. These operations affect brain excitability and their dysfunction can increase susceptibility to seizures and eventually lead to epilepsy. Importantly, ion homeostasis in astrocytes is fueled by astrocytic glycogen, the sole cerebral energy store. The primary aim of the present project is to investigate how metabolism of glycogen in astrocytes supports and influences the different stages of neuronal activity under normal and epileptogenic conditions. I hypothesize that K+-induced glycogenolysis in astrocytes controls neuronal excitability (functional role) as well as neuronal glucose uptake (metabolic role). These ideas are supported by the recently demonstrated requirement of astrocytic glycogenolysis for the uptake of extracellular K+ obtained in cell cultures and by preliminary results that I obtained through kinetic analysis. The present project will tackle, for the first time in awake behaving mice, the characterization of activity-dependent brain glycogen metabolism by means of electrophysiological and pharmacological experiments. The outcomes will provide essential insights into the mechanisms underlying normal ion homeostasis and its impairment in epilepsy as well as other pathologies related to aberrations in brain energy metabolism. The project will have a substantial impact on my career, as new skills in invasive experimental techniques on awake animals will complement my previous expertise in non-invasive functional magnetic resonance methods on human subjects.
Original text from CORDIS.
Participants
- KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark
Links
Data: CORDIS, © European Union