Biology Reference
In-Depth Information
PDE10A protein is observed in
g
-aminobutyric acid-(GABA) containing medium
spiny projection neurons of the mammalian striatum, which is the core site for
information integration and modulating motor and cognitive processing (Seeger
et al.
2003
; Menniti et al.
2006
). Therefore, it seems that PDE10A is an important
regulator of cGMP in the striatum and may be involved in the physiological
regulation of motor and cognitive function (Lehericy and Gerardin
2002
).
It is reported that inhibition of PDE10A causes a reduction of locomotor activity
and a failure to respond to psychomotor stimulants. Chronic PDE10A inhibition
produces a variety of behavioral and central neurochemical effects, which are
exacerbated by stress (Hebb et al.
2008
). PDE10A knockout mice exhibit decreased
exploratory activity and a significant delay in the acquisition of conditioned avoid-
ance behavior when compared to wild-type mice (Siuciak et al.
2006
). PDE10A
inhibition in primary neuronal cultures increases phosphorylation of CREB in the
nucleus; however, the functional significance of this effect is unclear (Menniti et al.
2006
). The most consistent series of findings regarding PDE10 inhibitors suggests
their potential for treatment of symptoms of schizophrenia.
3.11 PDE11
The most recently discovered of the PDE families is PDE11A, which catalyzes the
hydrolysis of cAMP and cGMP equally well (Francis
2005
; Yuasa et al.
2001
;
Weeks et al.
2007
). The first report of PDE11A was by Fawcett et al. (
2000
), who
identified a partial sequence from a commercially available expressed sequence tag
database based on homology with other mammalian PDEs (Makhlouf et al.
2006
).
Four splicing variants of PDE11A have been discovered, PDE11A1-4. PDE11A4 is
the longest variant with two N-terminal GAF domains, while the other variants are
truncated into shorter lengths (Bender and Beavo
2006
).
Initial studies suggested that PDE11A is found in skeletal muscle, prostate,
testis, pancreas, and salivary glands. Subsequent work showed that PDE11A is
also found in the brain, pituitary, and spinal cord (Fawcett et al.
2000
; Yuasa et al.
2001
). Recent findings reveal that PDE11A mRNA and protein in the brain are
largely restricted to hippocampus and subiculum, suggesting a potential role in
mood and cognitive function (Kelly et al.
2010
). This group showed that PDE11A
knockout mice exhibit subtle behavioral changes relevant to psychiatric disease,
including hyperactivity in an open field, increased sensitivity to the glutamate
NMDA receptor antagonist MK-801, and deficits in social behaviors (social odor
recognition memory and social avoidance). It has been speculated that PDE11A
may be one of the several genes playing a role in the multifactorial origin of
psychiatric diseases such as schizophrenia. A single nucleotide polymorphism
(SNP) analysis also suggests that PDE11 may be involved in processes affecting
depression and antidepressant drug response (Wong et al.
2006
).
Table
2
shows an overview of the effects of PDE inhibitors on behaviors related
to mood and cognitive disorders.
