Biology Reference
In-Depth Information
also a prominent feature in a variety of neurodegenerative and neuropsychiatric
disorders (Viana et al.
2010
) with various studies revealing the role of apoptosis in
the pathology of depression and anxiety where cGMP is likely to be inhibited
(Lucassen
2004
; Einat et al.
2005
). It is possible that PDE activities in these neuro-
psychiatric disorders may be altered leading to stimulation of a proapoptotic cascade
and symptoms associated with impaired learning and memory, depression, or anxiety.
Neuronal plasticity or remodeling is a critical process that underlies normal CNS
function by which the brain acquires information and makes the appropriate
adaptive responses in future-related settings (Rein
ยด
s et al.
2008
). Dysfunction of
neuronal plasticity could therefore contribute to the pathophysiology of mood
disorders and recovery could occur by induction of the appropriate plasticity or
remodeling phenomena (Akhondzadeh
1999
; Duman
2002
). Two aspects of neuro-
nal plasticity are important for information processing: plasticity of intrinsic excit-
ability, i.e., the change in ion channel properties; and synaptic plasticity, i.e.,
the change in the strength of synapses between neurons (Kotaleski and Blackwel
Kim
2010
). Synaptic plasticity is thought to underlie learning and memory, but the
complexity of the interactions between ion channels, enzymes, and genes that are
involved in synaptic plasticity impedes a deep understanding of this phenomenon
(Pereira and Furlan
2010
). Recently, Chen and colleagues (
2010
) found that
inhibition of mossy fiber LTP by acute stress originates from a sustained increase
in PDE4 activity, which accelerates the metabolism of cAMP to adenosine, in turn
triggering an adenosine receptor-mediated impairment of transmitter release
machinery. These results are supported by a more recent study, which indicated
that, PDE, cAMP, and its main effector PKA are critical for several aspects of
neuronal function including synaptic plasticity (Oliveira et al.
2010
).
5 Future Directions
Over the last five decades, great progress has been made in understanding the roles
of PDEs and their inhibitors in regulating CNS functions that are important for the
pathophysiology and treatment of neurological and psychiatric disorders. However,
the understanding of PDE function in the CNS is incomplete and requires further
investigation. First, it is necessary to obtain more knowledge about the localization
of specific PDE isoforms in different brain regions, cell types, and intracellular
compartments. Second, it would be helpful for more powerful tools to be developed
to characterize and manipulate individual PDE isoforms in situ and to identify their
involvement in signaling machinery. Third, it will be important that novel and
selective inhibitors be developed that have potential to selectively affect individual
subtypes and isoforms or to alter PDE function through allosteric interactions or by
disrupting interactions with scaffolding or auxiliary proteins. Such information and
tools will provide a better basis for the development of drugs to treat neurological
and psychiatric disorders.
