Role of presenilin1 in structural plasticity of cortical dendritic spines in vivo

• Published in: Journal of neurochemistry 2011-12, Vol.119 (5), p.1064-1073
• Main Authors: Jung, Christian K. E., Fuhrmann, Martin, Honarnejad, Kamran, Van Leuven, Fred, Herms, Jochen
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Alzheimer's disease; Amyloid precursor protein; beta -Amyloid; Biological and medical sciences; Calcium homeostasis; Calcium ions; Catalytic subunits; Cortex; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dendrites; Dendritic plasticity; dendritic spine; Dendritic spines; Dendritic structure; Density; Enzymes; familial Alzheimer’s disease; Homeostasis; Medical sciences; Memory; Neurochemistry; Neurodegenerative diseases; Neuroimaging; Neurology; Neurons; Neuroplasticity; Neurotoxicity; Organic mental disorders. Neuropsychology; Plasticity; Plasticity (cortical); Plasticity (dendritic); Plasticity (synaptic); Presenilin 1; presinilin; Proteins; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Ryanodine receptors; Secretase; Somatosensory cortex; Spine; structural plasticity; Synapses; Synaptic plasticity; Synaptogenesis; Transgenes; Transgenic mice; two‐photon in vivo microscopy; β-Amyloid
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2011.07503.x

J. Neurochem. (2011) 119, 1064–1073. Mutations in presenilins are the major cause of familial Alzheimer’s disease (FAD), leading to impairments of memory and synaptic plasticity followed by age‐dependent neurodegeneration. Presenilins are the catalytic subunits of γ‐secretase, which itself is critically involved in the processing of amyloid precursor protein to release neurotoxic amyloid β (Aβ). Besides Aβ generation, there is growing evidence that presenilins play an essential role in the formation and maintenance of synapses. To further elucidate the effect of presenilin1 (PS1) on synapses, we performed longitudinal in vivo two‐photon imaging of dendritic spines in the somatosensory cortex of transgenic mice over‐expressing either human wild‐type PS1 or the FAD‐mutated variant A246E (FAD‐PS1). Interestingly, the consequences of transgene expression were different in two subtypes of cortical dendrites. On apical layer 5 dendrites, we found an enhanced spine density in both mice over‐expressing human wild‐type presenilin1 and FAD‐PS1, whereas on basal layer 3 dendrites only over‐expression of FAD‐PS1 increased the spine density. Time‐lapse imaging revealed no differences in kinetically distinct classes of dendritic spines nor was the shape of spines affected. Although γ‐secretase‐dependent processing of synapse‐relevant proteins seemed to be unaltered, higher expression levels of ryanodine receptors suggest a modified Ca2+ homeostasis in PS1 over‐expressing mice. However, the conditional depletion of PS1 in single cortical neurons had no observable impact on dendritic spines. In consequence, our results favor the view that PS1 influences dendritic spine plasticity in a gain‐of‐function but γ‐secretase‐independent manner.