title: Enhanced long-term depression and impaired reversal learning in phosphodiesterase 4B-knockout (PDE4B-/-) mice.
abstract: 3'-5'-Cyclic adenosine monophosphate (cAMP) is known to be an important regulator of synaptic plasticity. The effects of cAMP are mediated through downstream effectors such as protein kinase A (PKA), Ca(2+) and cAMP-response element binding protein (CREB). The phosphodiesterase 4 (PDE4) family of enzymes, which is comprised of four genes and at least 25 protein isoforms, mediates the hydrolysis of cAMP, yet little is presently known about the contribution of specific PDE4 isoforms to synaptic plasticity and cognitive behavior. The purpose of the present studies was to determine the contribution of the PDE4B gene in mediating synaptic plasticity and cognitive behavior. Electrophysiological recordings from hippocampal slice preparations of mice deficient in the PDE4B gene (PDE4B(-/-)) showed that knockout animals displayed markedly enhanced basal postsynaptic responses to stimulation and long-term depression as compared to wild-type littermates. Interestingly, no genotypic differences were noted in long-term potentiation experiments following several different induction protocols. On the behavioral level PDE4B(-/-) mice displayed impaired reversal learning in the Morris water maze compared to wild-type littermates, but no differences in acquisition and retention of spatial memory and fear conditioning. Taken together, these results suggest that the PDE4B gene may play a role in synaptic activity and long-term depression and is involved in spatial reversal memory. Our findings support the view that various PDE4 isoforms are non-redundant and have distinct neurological roles.
authors: CNS Discovery Research, Roche Palo Alto, Palo Alto, CA, USA. kris.rutten@grunenthal.com
authors: Kris
authors: K
authors: Rutten
authors: Tanya L
authors: TL
authors: Wallace
authors: Melissa
authors: M
authors: Works
authors: Jos
authors: J
authors: Prickaerts
authors: Arjan
authors: A
authors: Blokland
authors: Thomas J
authors: TJ
authors: Novak
authors: Luca
authors: L
authors: Santarelli
authors: Dinah L
authors: DL
authors: Misner
mesh_terms: D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000172:deficiency* / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D012193:Reversal Learning / Q000502:physiology*
chemical_list: D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C543000:PDE4B protein, mouse