A study of long-term potentiation in transgenic mice over-expressing mutant forms of both amyloid precursor protein and presenilin-1.

Synaptic transmission and long-term potentiation (LTP) in the CA1 region of hippocampal slices have been studied during ageing of a double transgenic mouse strain relevant to early-onset familial Alzheimer's disease (AD). This strain, which over-expresses both the 695 amino acid isoform of human amyloid precursor protein (APP) with K670N and M671L mutations and presenilin 1 with the A246E mutation, has accelerated amyloidosis and plaque formation. There was a decrease in synaptic transmission in both wildtype and transgenic mice between 2 and 9 months of age. However, preparing slices from 14 month old animals in kynurenic acid (1 mM) counteracted this age-related deficit. Basal transmission and paired-pulse facilitation was similar between the two groups at all ages (2, 6, 9 and 14 months) tested. Similarly, at all ages LTP, induced either by theta burst stimulation or by multiple tetani, was normal. These data show that a prolonged, substantially elevated level of Abeta are not sufficient to cause deficits in the induction or expression of LTP in the CA1 hippocampal region.

Hippocampal synaptic plasticity in mice carrying the rd mutation in the gene encoding cGMP phosphodiesterase type 6 (PDE6).

Cyclic GMP (cGMP) has been implicated in the modulation of long-term potentiation (LTP) and depression (LTD) in the hippocampus. Transcripts for subunits of several types of cGMP specific phosphodiesterase are found in the mammalian brain but their relative role in hippocampal function is unclear. The retinal degeneration (rd) mutation in the gene encoding the PDE6B subunit causes a loss of function in PDE6 enzyme and in adult mice homozygous to the mutation it causes blindness. We have used this natural mutation, and the cGMP phosphodiesterase inhibitor zaprinast, in wild-type and rd/rd mouse littermates to investigate whether PDE5 and/or PDE6 regulates excitatory synaptic transmission in the hippocampus. Mice were genotyped using two independent PCR methods. Glutamate-mediated synaptic transmission in the CA1 region or dentate gyrus was unaffected in hippocampal brain slices from mice carrying the rd mutation. Similarly the facilitation of synaptic events by paired-pulse stimuli, and LTP induced by a theta-burst (10 bursts of four events at 100 Hz with a 200-ms inter-burst interval) were normal in rd/rd mice. Inhibition of cGMP-specific PDE activity by zaprinast (10 microM, an inhibitor of PDE5 and PDE6) induced a slowly developing and sustained depression of field synaptic potentials that was quantitatively similar in both wild-type and rd/rd mice. Thus in the CA1 region synaptic plasticity is likely to be regulated by the PDE5 rather than the PDE6 isoform.

Impairment in hippocampal long-term potentiation in mice under-expressing the Alzheimer's disease related gene presenilin-1.

Presenilin-1 (PS1) is intimately involved in cleavage of amyloid precursor protein to form beta-amyloid peptides, certain forms of which aggregate in the brains of patients with Alzheimer's disease (AD). The function(s) of PS1 and its precise involvement in the development of cognitive deficits associated with AD are unclear. We have utilised genetically modified mice that under-express PS1 (PS1(+/-) mice) to investigate the role of PS1 in hippocampal synaptic plasticity. Field excitatory postsynaptic responses elicited by baseline stimulation were indistinguishable between PS1(+/-) mice and wild-type controls. Likewise, a measure of short-term plasticity, paired-pulse facilitation, was normal in PS1(+/-) mice. However, long-term potentiation induced by multiple tetanus trains was reduced in PS1(+/-) animals. These results demonstrate that chronic reduction of PS1 activity leads to impaired synaptic plasticity, thus suggesting a role for PS1 in normal cognitive function.