cortex

Project number:

501

Project title:

Molecular mechanisms for regulation of extracellular space volume in brain

Project supervisor:

Amiry-Moghaddam, Nagelhus,Ottersen

Project description:

The extracellular space volume (ECSV) is a major determinant for the efficacy of volume transmission and transmitter and ion homeostasis in the CNS. Further, perturbations of ECSV are implicated in the pathophysiology of several neurological conditions including Alzheimer’s disease. It is not known to what extent the ECSV is subject to regulation and which signalling systems are involved. Our hypothesis is that ECSV is actively regulated through the activity and subcellular compartmentation of brain water channels – most notably AQP4. For example, an upregulation of AQP4 expression level around synaptic sites could modulate transmitter spillover to adjacent synapses. We propose to test our hypothesis by analysis of alpha syntrophin knockout mice and mice with AQP4 overexpression. Alpha syn-/- mice selectively lack the perivascular pool of AQP4, reflecting the central role of alpha syntrophin in the anchoring of AQP4 in perivascular astrocyte membranes. Diffusion weighted MR analysis of tetramethylammonium (Sykova’s lab) will be used to monitor the effects of the above gene manipulations on ECS – in the basal state and after hyponatremic stress. In collaboration with Frances Edward’s laboratory we will explore whether up- or downregulation of AQP4 affects transmitter spillover and LTP. Finally, a collaboration with Dr Dirnagl will be sought to resolve how AQP4 is anchored at non-endfeet membranes (by use of a proteomics approach). It is envisaged that these studies will clarify whether water channels are actively involved in regulating ECSV and, by inference, the concentrations of ions and metabolites in the extracellular fluid of the brain.

Possible cortex partners for rotation:

Dr Dirnagl, Dr Sykova, Dr Edwards
(see above for description of tasks)