Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein.
Abnormal processing of amyloid precursor protein (APP), in particular the generation of beta-amyloid (Abeta) peptides, has been implicated in the pathogenesis of Alzheimer's disease. This study examined the consequences of deleting the APP gene on hippocampal synaptic plasticity, and upon the biophysical properties of morphologically identified neurones in APP-null mice. The hippocampus of APP-null mice had a characteristic increase in gliosis throughout the CA1 region and a disruption of staining for the dendritic marker MAP2 and the presynaptic marker synaptophysin. The disruption of MAP2 staining was associated with a significant reduction in overall dendritic length and projection depth of biocytin labeled CA1 neurones. In two groups of APP-null mice that were examined at 8-12 months, and 20-24 months of age, there was an impairment in the formation of long-term potentiation (LTP) in the CA1 region compared to isogenic age matched controls. This LTP deficit was not associated with an alteration in the amplitude of EPSPs at low stimulus frequencies (0.033 Hz) or facilitation during a 100 Hz stimulus train, but was associated with a reduction in post-tetanic potentiation. Paired-pulse depression of GABA-mediated inhibitory post-synaptic currents was also attenuated in APP-null mice. These data demonstrate that the impaired synaptic plasticity in APP deficient mice is associated with abnormal neuronal morphology and synaptic function within the hippocampus.
Seabrook
G R
GR
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Smith
D W
DW
Bowery
B J
BJ
Easter
A
A
Reynolds
T
T
Fitzjohn
S M
SM
Morton
R A
RA
Zheng
H
H
Dawson
G R
GR
Sirinathsinghji
D J
DJ
Davies
C H
CH
Collingridge
G L
GL
Hill
R G
RG
D000375:Aging / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003712:Dendrites / Q000502:physiology / Q000648:ultrastructure; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005911:Gliosis; D006624:Hippocampus / Q000254:growth & development / Q000473:pathology / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D013569:Synapses / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D008869:Microtubule-Associated Proteins