Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition.
Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modeling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4B(Y358C) mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioral assays, PDE4B(Y358C) mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4B(Y358C) mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4B(Y358C) mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signaling by PDE4B in a very late phase of consolidation. No effect of the PDE4B(Y358C) mutation was observed in the prepulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory.
Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Alexander
A
McGirr
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Tatiana V
TV
Lipina
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Medical Genetics, University of Toronto, Toronto, Ontario, Canada.
Ho-Suk
HS
Mun
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
John
J
Georgiou
School of Biomedical Sciences, University of Leeds, Leeds, UK.|National Genetic Centre, Royal Hospital, Muscat, Oman.
Ahmed H
AH
Al-Amri
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Enoch
E
Ng
Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Dongxu
D
Zhai
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Christina
C
Elliott
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Ryan T
RT
Cameron
Institute of Life Science, College of Medicine, Swansea University, Swansea, UK.
Jonathan G L
JG
Mullins
Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Fang
F
Liu
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
George S
GS
Baillie
School of Biomedical Sciences, University of Leeds, Leeds, UK.
Steven J
SJ
Clapcote
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
John C
JC
Roder
D000679:Amygdala / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D000818:Animals; D001007:Anxiety / Q000201:enzymology*; D019390:Arrestins / Q000378:metabolism; D003214:Conditioning, Classical / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D049229:Dendritic Spines / Q000201:enzymology; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010766:Phosphorylation; D015398:Signal Transduction; D000071557:beta-Arrestins
D019390:Arrestins; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D000071557:beta-Arrestins; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4