Matthias Klugmann

Tau exacerbates excitotoxic brain damage in an animal model of stroke

Publisher: Springer Science and Business Media LLC

Date: 07-09-2017

DOI: 10.1038/S41467-017-00618-0

Abstract: Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau −/− ) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau −/− mice abolished the protection from pharmacologically induced excitotoxicity and middle cerebral artery occlusion-induced brain damage. Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. Our findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.

Mapping of bionic array electric field focusing in plasmid DNA-based gene electrotransfer

Publisher: Springer Science and Business Media LLC

Date: 30-01-2016

DOI: 10.1038/GT.2016.8

TRPC Channels Activated by G Protein-Coupled Receptors Drive Ca2+ Dysregulation Leading to Secondary Brain Injury in the Mouse Model

Publisher: Springer Science and Business Media LLC

Date: 18-07-2023

DOI: 10.1007/S12975-023-01173-1

Abstract: Canonical transient receptor potential (TRPC) non-selective cation channels, particularly those assembled with TRPC3, TRPC6, and TRPC7 subunits, are coupled to G αq -type G protein-coupled receptors for the major classes of excitatory neurotransmitters. Sustained activation of this TRPC channel-based pathophysiological signaling hub in neurons and glia likely contributes to prodigious excitotoxicity-driven secondary brain injury expansion. This was investigated in mouse models with selective Trpc gene knockout (KO). In adult cerebellar brain slices, application of glutamate and the class I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine to Purkinje neurons expressing the GCaMP5g Ca 2+ reporter demonstrated that the majority of the Ca 2+ loading in the molecular layer dendritic arbors was attributable to the TRPC3 effector channels ( Trpc3 KO compared with wildtype (WT)). This Ca 2+ dysregulation was associated with glutamate excitotoxicity causing progressive disruption of the Purkinje cell dendrites (significantly abated in a GAD67-GFP - Trpc3 KO reporter brain slice model). Contribution of the G αq -coupled TRPC channels to secondary brain injury was evaluated in a dual photothrombotic focal ischemic injury model targeting cerebellar and cerebral cortex regions, comparing day 4 post-injury in WT mice, Trpc3 KO , and Trpc1/3/6/7 quadruple knockout ( Trpc QKO ), with immediate 2-h (primary) brain injury. Neuroprotection to secondary brain injury was afforded in both brain regions by Trpc3 KO and Trpc QKO models, with the Trpc QKO showing greatest neuroprotection. These findings demonstrate the contribution of the G αq -coupled TRPC effector mechanism to excitotoxicity-based secondary brain injury expansion, which is a primary driver for mortality and morbidity in stroke, traumatic brain injury, and epilepsy.

Acetate metabolism does not reflect astrocytic activity, contributes directly to GABA synthesis, and is increased by silent information regulator 1 activation

Publisher: Wiley

Date: 23-01-2017

DOI: 10.1111/JNC.13916

Abstract: [

L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism

Publisher: Springer Science and Business Media LLC

Date: 18-05-2020

DOI: 10.1007/S11064-020-03044-9

Correction to: L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism (Neurochemical Research, (2020), 45, 6, (1438-1450), 10.1007/s11064-020-03044-9)

Publisher: Springer Science and Business Media LLC

Date: 07-07-2020

DOI: 10.1007/S11064-020-03087-Y

ARC Future Fellowships - Grant ID: FT100100546

Start Date: 02-2011

End Date: 06-2015

Amount: $803,217.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP140101008

Start Date: 06-2015

End Date: 12-2018

Amount: $350,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP150104754

Start Date: 02-2015

End Date: 12-2018

Amount: $384,700.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100027

Start Date: 04-2012

End Date: 12-2013

Amount: $320,000.00

Funder: Australian Research Council