Abstract
Aβ peptides derived from the cleavage of amyloid precursor protein are widely believed to play an important role in the pathophysiology of Alzheimer's disease. A common way to study the impact of these molecules on CNS function is to compare the physiology of transgenic mice that overproduce Aβ with non-transgenic animals. In the hippocampus, this approach has been frequently applied to the investigation of synaptic transmission and plasticity in the perforant and Schaffer collateral commissural pathways, the first and third components of the classical hippocampal trisynaptic circuit, respectively. Similar studies however have not been carried out on the remaining component of the trisynaptic circuit, the mossy fibre pathway. Using transverse hippocampal slices prepared from ~2 year old animals we have compared mossy fibre synaptic function in wild-type mice and their Tg2576 littermates which age-dependently overproduce Aβ. Input-output curves were not altered in slices from Tg2576 mice, but these animals exhibited a significant loss of the prominent frequency-facilitation expressed by the mossy fibre pathway. In addition to this change in short term synaptic plasticity, high frequency stimulation-induced, NMDA-receptor-independent LTP was absent in slices from the transgenic mice. These data represent the first description of functional deficits in the mossy fibre pathway of Aβ-overproducing transgenic mice.
Highlights
The hippocampus is a brain structure with a crucial role in mammalian learning and memory
The three sequential glutamatergic pathways that make up this circuit are 1) the perforant path (PP) inputs to the granule cells of the dentate gyrus (DG-GC), 2) the mossy fibre projection (MFP) from DG-GCs to CA3 pyramidal cells (CA3-PC) and, 3) the Schaffer collateral commissural pathway (SCCP) that links CA3-PCs with CA1 pyramidal cells (CA1-PC)
MFP responses in slices from both aged WT and Tg2576 mice exhibited marked paired pulse facilitation (PPF) (Figure 1B); at all inter-stimulus latencies PPF in the Tg2576 group (n = 8) was between 5 and 10% less that than that in the WT group (n = 8), indicating that short term synaptic plasticity might be disturbed in the amyloid beta peptide (Ab)-overproducing mice
Summary
The hippocampus is a brain structure with a crucial role in mammalian learning and memory. In transverse section the hippocampus has an iconic morphology around which a trisynaptic loop of glutamatergic pathways navigates. The three sequential glutamatergic pathways that make up this circuit are 1) the perforant path (PP) inputs to the granule cells of the dentate gyrus (DG-GC), 2) the mossy fibre projection (MFP) from DG-GCs to CA3 pyramidal cells (CA3-PC) and, 3) the Schaffer collateral commissural pathway (SCCP) that links CA3-PCs with CA1 pyramidal cells (CA1-PC). There are a large number of neurological and psychiatric diseases in which measurable cognitive deficits contribute to the disease phenotype. Of these Alzheimer’s disease (AD) is perhaps the best known. The prevalence of this condition means that most adults in the developed world will have personal experience from friends
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