Mutant presenilin 1 alters synaptic transmission in cultured hippocampal neurons.
Mutations in presenilins are the major cause of familial Alzheimer disease, but the precise pathogenic mechanism by which presenilin (PS) mutations cause synaptic dysfunction leading to memory loss and neurodegeneration remains unclear. Using autaptic hippocampal cultures from transgenic mice expressing human PS1 with the A246E mutation, we demonstrate that mutant PS1 significantly depressed the amplitude of evoked alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptor-mediated synaptic currents. Analysis of the spontaneous miniature synaptic activity revealed a lower frequency of miniature currents but normal miniature amplitude. Both alterations could be rescued by the application of a gamma-secretase blocker. On the other hand, the application of synthetic soluble Abeta42 in wild-type neurons induced the PS1 mutant phenotype on synaptic strength. Together, these findings strongly suggest that the expression of mutant PS1 in cultured neurons depresses synaptic transmission by causing a physical reduction in the number of synapses. This hypothesis is consistent with morphometic and semiquantitative immunohistochemical analysis, revealing a decrease in synaptophysin-positive puncta in PS1 mutant hippocampal neurons.
Priller
Christina
C
Department of Neuropathology, Ludwig-Maximilians-Universität Munich, Feodor-Lynen-Strasse 23, 81377 München, Germany.
Dewachter
Ilse
I
Vassallo
Neville
N
Paluch
Sandra
S
Pace
Claudia
C
Kretzschmar
Hans A
HA
Van Leuven
Fred
F
Herms
Jochen
J
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D053764:Presenilin-1 / Q000235:genetics*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013572:Synaptic Vesicles / Q000502:physiology; D016708:Synaptophysin / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D004151:Dipeptides; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; C492933:N-(N-(3,5-difluorophenylacetyl)alanyl)phenylglycine 4-benzoylbenzyl amide; D053764:Presenilin-1; D016708:Synaptophysin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D053829:Amyloid Precursor Protein Secretases