Abstract
Dendritic spines are postsynaptic structures in neurons often having a mushroom-like shape. Physiological significance and cytoskeletal mechanisms that maintain this shape are poorly understood. The spectrin-based membrane skeleton maintains the biconcave shape of erythrocytes, butwhetherspectrins alsodeterminetheshapeofnonerythroidcells is less clear.Weshowthat βIII spectrin inhippocampalandcortical neuronsfromrodentembryosof both sexes is distributed throughout the somatodendriticcompartmentbut is particularly enriched in the neck and base of dendritic spines and largely absent from spine heads. Electron microscopy revealed thatβIII spectrin forms a detergent-resistant cytoskeletal network at these sites. Knockdown of βIII spectrin results in a significant decrease in the density of dendritic spines. Surprisingly, the density of presynaptic terminals is not affected by βIII spectrin knockdown. However, instead of making normal spiny synapses, the presynaptic structures in βIII spectrin-depleted neurons make shaft synapses that exhibit increased amplitudes of miniature EPSCs indicative of excessive postsynaptic excitation. Thus, βIII spectrin is necessary for formation of the constricted shape of the spine neck, which in turn controls communication between the synapse and the parent dendrite to prevent excessive excitation. Notably, mutations of SPTNB2 encoding βIII spectrin are associated with neurodegenerative syndromes, spinocerebellar ataxia Type 5, and spectrin-associated autosomal recessive cerebellar ataxiaType1,butmolecularmechanismslinking βIII spectrin functions toneuronalpathologiesremainunresolved.Ourdatasuggest that spinocerebellar ataxia Type 5 and spectrin-associated autosomal recessive cerebellar ataxia Type 1 pathology likely arises from poorly controlled synaptic activity that leads to excitotoxicity and neurodegeneration.
Original language | English (US) |
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Pages (from-to) | 6442-6459 |
Number of pages | 18 |
Journal | Journal of Neuroscience |
Volume | 37 |
Issue number | 27 |
DOIs | |
State | Published - 2017 |
Keywords
- Cytoskeleton
- Dendritic spines
- Electron microscopy
- Hippocampal neurons
- Spectrin
- Synapse
ASJC Scopus subject areas
- Neuroscience(all)