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Numata et al.
2008
; Fatemi et al.
2008
). Another important finding is the interaction
of endogenous disrupted-in-schizophrenia 1 (DISC1) and PDE4B in schizophrenia
(Millar et al.
2005
; Siuciak et al.
2008
; Clapcote et al.
2007
). DISC1 is a genetic
susceptibility factor for schizophrenia and is a multifunctional scaffold protein that
is able to interact with several proteins, including PDE4B (Millar et al.
2005
;
Clapcote et al.
2007
). The PDE4B-specific binding sites encompass point mutations
in mouse DISC1 that confer phenotypes related to schizophrenia and depression
(Murdoch et al.
2007
). We speculate that functional variation in DISC1 and PDE4
will modulate their interaction and affect cAMP signaling.
PDE4D knockout mice exhibit significant changes in associative learning (i.e.,
fear conditioning) and a reduction of immobility in the forced-swim and tail
suspension tasks (Rutten et al.
2008
; Zhang et al.
2002a
,
b
). Inhibition of the
residual PDE4 subtypes in PDE4D knockout mice (i.e., PDE4A and PDE4B) by
repeated treatment with rolipram does not result in further antidepressant-like
effects on behavior (Zhang et al.
2002a
,
b
). Consistent with this, PDE4D is highly
expressed in the hippocampus, a sensitive structure in controlling the progression of
depression and memory operations, including the formation of stable declarative
(or explicit) memory in humans and spatial (or relational/contextual) memory in
rodents. These results provide the evidence that PDE4D may play a crucial role in
the mediation of antidepressant activity and memory (Rutten et al.
2008
; Zhang
et al.
2008
). This is supported by findings that PDE4D is the most consistent
subtype upregulated by repeated antidepressant treatment of mice, suggesting the
involvement of this subtype in signaling pathways critical for these functions
(Dlaboga et al.
2006
).
It is possible that PDE4A also might be a particularly attractive target for
regulating depression and associated cognitive deficits, since it is found to distribute
in a similar pattern as PDE4D in the brain (Takahashi et al.
1999
). Consistent with
this notion, it has been found that the PDE4A subtype in neuronal cultures is
regulated in response to changes in NMDA receptor function, suggesting a possible
role in cAMP signaling in memory-related processes such as long-term potentiation
(Hajjhussein et al.
2007
). Evaluation of the behavioral phenotype of PDE4A
knockout mice would begin to define the functional role for this subtype in the
brain. Recent studies suggested that the PDE4A5 protein is significantly increased
in memory deficits induced by sleep deprivation, which can be reversed by rolipram
(Vecsey et al.
2009
). The interaction between cognitive impairment and PDE4A5
shows that it may be possible to develop compounds that block either the activity or
targeting of the PDE4A5 isoform for treatment of cognitive impairment and related
sleep disorders.
3.5 PDE5
PDE5 was initially identified and characterized from platelets and then lung (Coquil
et al.
1980
; Francis et al.
1980
). However, its regulation of smooth muscle
