Cell-Specific Loss of SNAP25 from Cortical Projection Neurons Allows Normal Development but Causes Subsequent Neurodegeneration
| Autor: | Helen C. Christian, Ege T. Kavalali, Zoltán Molnár, Eleanor Grant, Shuichi Hayashi, Denise M.O. Ramirez, Anna Hoerder-Suabedissen, Alexander Jeans, Kim K.V. Korrell, Michael Wilson |
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| Rok vydání: | 2018 |
| Předmět: |
Male
endocrine system Synaptosomal-Associated Protein 25 Neurite Cognitive Neuroscience Axonal loss Hippocampal formation Biology Synaptic Transmission Synaptic vesicle 050105 experimental psychology 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Conditional gene knockout medicine Animals 0501 psychology and cognitive sciences Patch clamp Mice Knockout Neurons 05 social sciences Neurodegeneration Brain SNAP25 Original Articles medicine.disease Axons Cell biology nervous system Female Synaptic Vesicles 030217 neurology & neurosurgery |
| Zdroj: | Cereb Cortex |
| ISSN: | 1460-2199 1047-3211 |
| DOI: | 10.1093/cercor/bhy127 |
| Popis: | Synaptosomal associated protein 25 kDa (SNAP25) is an essential component of the SNARE complex regulating synaptic vesicle fusion. SNAP25 deficiency has been implicated in a variety of cognitive disorders. We ablated SNAP25 from selected neuronal populations by generating a transgenic mouse (B6-Snap25tm3mcw (Snap25-flox)) with LoxP sites flanking exon5a/5b. In the presence of Cre-recombinase, Snap25-flox is recombined to a truncated transcript. Evoked synaptic vesicle release is severely reduced in Snap25 conditional knockout (cKO) neurons as shown by live cell imaging of synaptic vesicle fusion and whole cell patch clamp recordings in cultured hippocampal neurons. We studied Snap25 cKO in subsets of cortical projection neurons in vivo (L5—Rbp4-Cre; L6—Ntsr1-Cre; L6b—Drd1a-Cre). cKO neurons develop normal axonal projections, but axons are not maintained appropriately, showing signs of swelling, fragmentation and eventually complete absence. Onset and progression of degeneration are dependent on the neuron type, with L5 cells showing the earliest and most severe axonal loss. Ultrastructural examination revealed that cKO neurites contain autophagosome/lysosome-like structures. Markers of inflammation such as Iba1 and lipofuscin are increased only in adult cKO cortex. Snap25 cKO can provide a model to study genetic interactions with environmental influences in several disorders. |
| Databáze: | OpenAIRE |
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