Biology Reference
In-Depth Information
underlying the expression and reduction of fear may help improve pharmacologic
treatments for emotion-related memory disorders.
In addition, PDE4 inhibitors reverse working memory deficits caused by the
NMDA receptor antagonist (MK-801), MEK inhibition, electroconvulsive shock
(ECS), and age- or microsphere embolism-induced cerebral ischemia in the radial-
arm maze and the three-panel runway task (Zhang et al.
2004
,
2005
; Reneerkens
et al.
2009
). Another study has shown that two novel PDE4 inhibitors, MEM1018
and MEM1091, improve memory processes in radial-arm maze and passive avoid-
ance tests (Zhang et al.
2005
). Consistent with these behavioral data, the PDE4
inhibitors produce parallel and consistent effects on cAMP concentrations in
cultured neurons that are pharmacologically altered through inhibition of NMDA
receptors or MEK (Suvarna and O'Donnell
2002
; Zhang et al.
2004
).
It has been reported that the effects of rolipram infusion into prefrontal cortex on
working memory in young and aged animals are different. It improves working
memory in young rhesus monkeys in a delayed responding task in a T-maze test,
but has a negative effect on working memory in aged monkeys in this task (Ramos
et al.
2003
,
2006
). The underlying mechanism may involve aged animals with
prefrontal cortical cognitive deficits being more sensitive to both the impairing
effects of PKA activation and the enhancing effects of PKA inhibition (Ramos et al.
2006
). Molecular analyses show that the basal PKA levels (i.e., regulatory or
catalytic subunit immunoreactivity) are changed in aged prefrontal cortex, but the
levels in hippocampus are not affected by aging. Moreover, CRE binding is
significantly higher in the aged prefrontal cortex but not in the hippocampus
(Ramos et al.
2003
). It is known that the increase in CRE binding may indirectly
reflect increased PKA activity since activation of this pathway has been shown
to upregulate CRE-mediated gene expression, including the cAMP responsive
element binding protein (CREB) gene itself (Coven et al.
1998
). Although activation
of the cAMP/PKA pathway in the hippocampus has been proposed as a mechanism
for improving age-related cognitive impairment, the deficits in prefrontal cortex
function with advancing age have received increasing attention, particularly in
human and nonhuman primates. The prefrontal cortex is engaged during the
retrieval and encoding of memories and is critical for inhibition of proactive
interference, for protecting memories and thoughts from distraction, and for allow-
ing the planning and organization of behavior (Bunge et al.
2001
; Lepage et al.
2000
). Consistent with this, PDE4 is highly expressed in the prefrontal cortex and
hippocampus (Reneerkens et al.
2009
), which makes a predominant contribution to
cAMP hydrolysis in the brain and plays an important role in emotion and memory
processing. Recent, exciting data suggest that activation of cAMP-dependent pro-
tein kinase A is crucial for long-term potentiation and long-term depression (LTD)
of synaptic transmission in the hippocampus, phenomena that are thought to be
involved in memory formation (Ster et al.
2009
; Whitaker and Wei
2009
). The
studies reported the role of an alternative target of cAMP, the exchange protein
factors directly activated by cAMP (Epac1 and Epac2) that belong to a large family
of guanine exchange factor proteins that catalyze the activation of small G-proteins,
particularly Rap1 and Rap2 (Ster et al.
2009
; Bos
2006
). The results showed
