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Speaker Detail

Professor Anja Teschemacher

University of Bristol, UK

Biography

Dr. Teschenmachers main interests are the inter- and  intracellular signalling mechanisms which control release of  noradrenaline and adrenaline from central neurones. More specifically her group is focusing on the following:
- How does neuronal and astroglial activity link to release of noradrenaline?
- Which intracellular second messenger pathways are responsible for modulating release properties?
- What are the physiological consequences of release, for example, for central control of blood pressure or nociception?
They are addressing these questions by using a combination of  electrophysiological (patch clamp; amperometry; fast scan cyclic  voltammetry), optical (confocal imaging of living brain slice cultures;  cell-specific optogenetic stimulation), molecular (viral gene transfer)  and pharmacological tools.

Abstract

Viral vector tools for selective inhibition of lactate release from astrocytes

AG Teschemacher, B Vaccari Cardoso, V Mosienko, BH Liu, S Kasparov

Astrocytes are thought to be the main source of extracellular L-lactate (LL) in the brain under physiological conditions. LL levels respond dynamically to neuronal network activity and metabolic triggers and may serve neurones as additional energy substrate during periods of high activity. In addition, increasing evidence indicates that LL may have a signalling role in the brain and this could have implications for regulation of sleep/wake and attention states, learning and memory, and cardiorespiratory control.

We currently lack the means for selective manipulation of LL release from astrocytes for further investigation of its actions in the brain. We therefore set out to develop an array of astrocyte-selective viral vectors that will allow us to specifically limit LL release by expressing enzymes which break down or decrease LL synthesis. Such enzymes can be 'borrowed' from bacteria, for example D-lactate dehydrogenase (DLDH; EC 1.1.1.28), lactate monooxygenase (LMO; E.C. 1.13.12.4), or L-lactate oxidase (LOx; E.C. 1.1.3.15). DLDH catalyses the NADH-dependent reversible conversion of pyruvate to DL, instead of the LL which mammalian cells produce normally. LMO is an oxidoreductase which decarboxylates LL to acetate with comparatively slow kinetics. LOx, in contrast, rapidly converts LL to pyruvate, releasing peroxide as a by-product. Each of these strategies has its merits and potential limitations which we are currently investigating.

We show, using imaging, fluorimetry, and amperometry, in HEK293 cells and primary astrocytes, that prototypes of these constructs significantly decrease intracellular LL pool sizes (see also poster by B Vaccari Cardoso). We anticipate that astrocyte-selective expression of these novel constructs via adeno- and lentiviral vectors will facilitate studies into brain energy metabolism and central metabolic signalling.


All sessions by Professor Anja Teschemacher

  • MondayApril 9
10:55 AM

"Viral vector tools for selective inhibition of lactate release from astrocytes"