S. GELMAN, J. SANCHEZ-PADILLA, J. PALMA, P. KABTIZKE, G. TOMBAUGH, A. GHAVAMI
PsychoGenics, Montvale, NJ
Neurofibrillary tangles with accelerated amyloidosis and plaque formation are widely thought to play a major role in development of Alzheimer’s disease pathology. The rTg4510 mouse, a model of tauopathy, overexpresses P301L mutant human Tau in the forebrain. The APP/PS1 transgenic mouse overexpresses mutated forms of the genes for human amyloid precursor protein (APPsw) and presenilin 1 (m146L) and is used to study amyloid deposition. Generally, these lines of mice exhibit an age-dependent and region-specific progression of neuropathology. Additionally, synaptic dysfunction is evident in early development of pathology. However, there is no consensus about the extent to which basal synaptic transmission (BST) and synaptic plasticity are affected in these models. We used extracellular field potential recordings to study BST, short-term plasticity (PTP, post-tetanic potentiation; PPF, paired-pulse facilitation) and long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapses in young and old rTg4510 (2-3 and 6-7 month old) and old APP/PS1 mice (8-10 month old). We find that old but not young rTg4510 mice exhibit a correlated reduction in pre-synaptic fiber volley (FV) amplitude (~50%) and field excitatory post-synaptic potential (fEPSP) slope (~40%) compared to WT, consistent with hippocampal neurodegeneration. We also find that BST per se is not altered in this model, since fEPSP slope, controlled for FV amplitude, remained unchanged. In contrast, old APP/PS1 mice did not show reduced FV amplitude compared to WT, while fEPSP slope was reduced by ~34%, suggesting a deficit in BST. PTP was reduced in old APP/PS1 mice compared to WT, but not in old rTg4510 mice. PPF was unchanged in old APP/PS1 compared to WT, but was reduced in old rTg4510 mice. LTP, induced with high-frequency stimulation, was reduced in old rTg4510 and APP/PS1 mice. Our data suggest that APP/PS1 mice show reduced BST. In rTg4510 mice, early onset of neurodegeneration may mask BST dysfunction. However, PPF was reduced in rTg4510 mice suggesting some pre-synaptic alteration in remaining neurons. In APP/PS1 mice LTP reduction may be due to induction deficits, since they exhibit both reduced BST and PTP. The basis of the LTP deficit in rTg4510 mice remains unclear.