Affiliations: [a] Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA | [b] Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, CO, USA | [c] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA | [d] Max Planck Institute of Neurobiology, Martinsreid, Munich, Germany
Correspondence:
[*]
Corresponding author: James R. Bamburg, Department of Biochemistry and Molecular Biology, 1870 Campus Delivery, Colorado State University, Fort Collins, CO 80523-1870, USA. Tel.: +1 970 491 6096; Fax: +1 970 491 0494; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: Dissociated hippocampal neurons exposed to a variety of degenerative stimuli form neuritic cofilin-actin rods. Here we report on stimulus driven regional rod formation in organotypic hippocampal slices. Ultrastructural analysis of rods formed in slices demonstrates mitochondria and vesicles become entrapped within some rods. We developed a template for combining and mapping data from multiple slices, enabling statistical analysis for the identification of vulnerable sub-regions. Amyloid-β (Aβ) induces rods predominantly in the dentate gyrus region, and Aβ-induced rods are reversible following washout. Rods that persist 24 h following transient (30 min) ATP-depletion are broadly distributed, whereas rods formed in response to excitotoxic glutamate localize within and nearby the pyramidal neurons. Time-lapse imaging of cofilin-GFP-expressing neurons within slices shows neuronal rod formation begins rapidly and peaks by 10 min of anoxia. In ∼50% of responding neurons, Aβ-induced rod formation acts via cdc42, an upstream regulator of cofilin. These new observations support a role for cofilin-actin rods in stress-induced disruption of cargo transport and synaptic function within hippocampal neurons and suggest both cdc42-dependent and independent pathways modulate cofilin activity downstream from Aβ.
