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2016 ; 41
(4
): 1080-92
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Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates
Memory Acquisition
#MMPMID26272049
McGirr A
; Lipina TV
; Mun HS
; Georgiou J
; Al-Amri AH
; Ng E
; Zhai D
; Elliott C
; Cameron RT
; Mullins JG
; Liu F
; Baillie GS
; Clapcote SJ
; Roder JC
Neuropsychopharmacology
2016[Mar]; 41
(4
): 1080-92
PMID26272049
show ga
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 ?-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.
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