Biology Reference
In-Depth Information
that pharmacological activation of Epac by the selective agonist 8-(4-chlorophe-
nylthio)-2-
O
-methyl-cAMP (8-pCPT) induces LTD in the CA1 region. The
8-pCPT-induced LTD was blocked by the Epac signaling inhibitor, Rap-1 antagonist
and p38 mitogen-activated protein kinase (P38-MAPK) inhibitor. This indicates
a direct involvement of Epac in LTD. In addition, the activation of Epac2 and
Rap guanine-nucleotide exchange factor (GEF) induces synapse remodeling and
depression in cultured rat cortical neurons, which contributes to neural circuit
development and plasticity of brain circuits throughout life (Woolfrey et al.
2009
;
Holtmaat et al.
2005
;Orayetal.
2004
).
PKA activation affects learning and memory through downstream phosphoryla-
tion events, gene regulation, and synapse remodeling (Nguyen and Woo
2003
;
Woolfrey et al.
2009
). Infusions of the PKA activator Sp-cAMPs or PDE4 inhibitor
rolipram into the aged brain impairs or improves working memory performance
under conditions that require hippocampal-prefrontal cortex interactions (Taylor
et al.
1999
; Birnbaum et al.
1999
; Ramos et al.
2006
). Additional research is
necessary to identify the role of PDE4 in age-related behavioral changes, as well
as mechanisms that regulate PKA activity.
The deposition of beta-amyloid in the cerebral cortex and hippocampus is
considered as an early and critical event in the pathogenesis of age-related mood
and cognitive disorders associated with Alzheimer's disease. Recent studies have
shown that repeated treatment with rolipram reverses memory deficits in the water
maze and passive avoidance tasks induced by Abeta 25-35 or Abeta 1-40 (Cheng
et al.
2010
). The cognition enhancement by rolipram appears to be attributed
to rolipram-induced increases in cAMP/CREB signaling in the hippocampus.
These findings are in agreement with rolipram-induced reversal of memory deficits
in APP/PS1 transgenic mice (Gong et al.
2004
). However, the involvement of
particular PDE4 subtypes in mediating cognition has yet to be elucidated.
Schizophrenia has a complex genetic underpinning, and variations in a number
of candidate genes have been identified that confer risk of developing the disorder
(Fatemi et al.
2008
). The PDE4B gene is located at 1p31 that is a susceptibility
region for schizophrenia (Numata et al.
2008
; Pickard et al.
2007
). Significant
changes between wild-type and PDE4B knockout mice have been found in several
behavioral tasks, e.g., decreases in baseline levels of monoamines and their meta-
bolites in the striatum, decreased baseline motor activity, and an exaggerated
locomotor response to amphetamine (Siuciak et al.
2008
). These data suggest a
role for PDE4B in neuropsychiatric diseases and striatal function. Studies in our
laboratory (Zhang et al.
2008
) have found that PDE4B knockout mice display
anxiogenic-like behaviors, as evidenced by decreased head-dips and time spent in
head-dipping in the hole board test, reduced transitions and time on the light side in
the light-dark transition test, and decreased initial exploration and rears in the open-
field test; inconsistent effects were found in models of antidepressant sensitivity.
Neurochemical studies (Takahashi et al.
1999
) suggest that PDE4B in the frontal
cortex and nucleus accumbens, but not the hippocampus, is upregulated by chronic
antidepressant administration. The reports from clinical studies further support the
genetic linkage of PDE4B with schizophrenia in some patients (Pickard et al.
2007
;
