Rewiring neuronal microcircuits of the brain via spine head protrusions--a role for synaptopodin and intracellular calcium stores.
Neurological diseases associated with neuronal death are also accompanied by axonal denervation of connected brain regions. In these areas, denervation leads to a decrease in afferent drive, which may in turn trigger active central nervous system (CNS) circuitry rearrangement. This rewiring process is important therapeutically, since it can partially recover functions and can be further enhanced using modern rehabilitation strategies. Nevertheless, the cellular mechanisms of brain rewiring are not fully understood. We recently reported a mechanism by which neurons remodel their local connectivity under conditions of network-perturbance: hippocampal pyramidal cells can extend spine head protrusions (SHPs), which reach out toward neighboring terminals and form new synapses. Since this form of activity-dependent rewiring is observed only on some spines, we investigated the required conditions. We speculated, that the actin-associated protein synaptopodin, which is involved in several synaptic plasticity mechanisms, could play a role in the formation and/or stabilization of SHPs. Using hippocampal slice cultures, we found that ~70 % of spines with protrusions in CA1 pyramidal neurons contained synaptopodin. Analysis of synaptopodin-deficient neurons revealed that synaptopodin is required for the stability but not the formation of SHPs. The effects of synaptopodin could be linked to its role in Ca(2+) homeostasis, since spines with protrusions often contained ryanodine receptors and synaptopodin. Furthermore, disrupting Ca(2+) signaling shortened protrusion lifetime. By transgenically reintroducing synaptopodin on a synaptopodin-deficient background, SHP stability could be rescued. Overall, we show that synaptopodin increases the stability of SHPs, and could potentially modulate the rewiring of microcircuitries by making synaptic reorganization more efficient.
Integrated Program in Neuroscience, McGill University, Montreal, QC, H3G 0B1, Canada.
David
D
Verbich
Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, D-60590, Frankfurt/Main, Germany.|Department of Pharmacology and Therapeutics, McGill University, Bellini Life Sciences Building, Room 167, Montreal, QC, H3G 0B1, Canada.|Present address: Department of Fundamental Neurosciences, University of Lausanne, 1005, Lausanne, Switzerland.
Denise
D
Becker
Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, D-60590, Frankfurt/Main, Germany.|Present address: Institute of Anatomy II, Faculty of Medicine, Heinrich-Heine-University, D-40225, Düsseldorf, Germany.
Andreas
A
Vlachos
Harvard Medical School and Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
Peter
P
Mundel
Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, D-60590, Frankfurt/Main, Germany.
Thomas
T
Deller
Integrated Program in Neuroscience, McGill University, Montreal, QC, H3G 0B1, Canada. anne.mckinney@mcgill.ca.|Department of Pharmacology and Therapeutics, McGill University, Bellini Life Sciences Building, Room 167, Montreal, QC, H3G 0B1, Canada. anne.mckinney@mcgill.ca.
R Anne
RA
McKinney
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D021621:Imaging, Three-Dimensional; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism*; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007211:Indoles; D026941:Sodium Channel Blockers; D016708:Synaptophysin; C504261:Synpr protein, mouse; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; D002118:Calcium; C000543:cyclopiazonic acid
Calcium; Dendritic spines; Ryanodine; Structural plasticity; Synaptopodin