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

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.