Biology Reference
In-Depth Information
PDE4 inhibitors of nausea and emesis may be related to the high expression of
PDE4, particularly the PDE4D subtype, in the area postrema (Mori et al.
2010
).
In the brain, PDE5 is mainly distributed in cerebral cortex, pyramidal cells of the
hippocampus, basal ganglia, and most abundantly cerebellum (van Staveren et al.
2003
; Kleppisch
2009
; Garthwaite and Boulton
1995
).
PDE6 is confined to the retina and pineal gland and appears to play no direct role
in mediating psychopharmacological effects on behavior (Bender and Beavo
2006
).
High PDE7A mRNA signal intensities are detected in the hippocampus, olfac-
tory bulb and tubercle, and brainstem nuclei (Miro et al.
2001
), while PDE7B is
present in both neuronal and nonneuronal cell populations in multiple brain regions,
such as cerebellum, striatal complex, dentate gyrus of hippocampus, and in several
thalamic nuclei (P´rez-Torres et al.
2003
; Sasaki et al.
2002
).
PDE8A transcripts are rich in peripheral tissues, while PDE8B transcripts are
found in all brain regions of rats other than cerebellum and have been shown to exist
in neurons (Kobayashi et al.
2003
).
PDE9 signals are strong in cerebellar Purkinje cells, cerebral cortex, and hippo-
campus (van Staveren et al.
2001
,
2003
). Neuronal PDE9 expression has been
detected in the cerebellum, cerebral cortex, caudate-putamen, and hippocampus.
The dual-specificity PDE10 family is encoded by one gene, PDE10A, which has
emerged as a key therapeutic target for treatment of schizophrenia (Siuciak
2008
;
Kelly and Brandon
2009
). It is interesting that the apparent function of PDE10A
relates to its unique distribution in the brain, which is very high in the caudate-
putamen, nucleus accumbens, and olfactory tubercle, with minimal expression in
cortex, hippocampus, and cerebellum (Kelly et al.
2010
).
The PDE11 family is the most recently described PDE family and also contains
one gene, PDE11A; four splice variants have been described (Loughney et al.
2005
). PDE11A mRNA and protein are largely restricted to the hippocampus,
with two- to threefold enrichment in the ventral vs. dorsal hippocampus, equal
distribution between cytosolic and membrane fractions, and increasing levels of
protein expression from postnatal day 7 through adulthood (Kelly et al.
2010
).
The relative distribution patterns of the different PDE isoforms in the brain are
shown in Table
1
. The differential expression patterns of PDEs in the brain and
their roles in controlling neuronal activity indicate that targeted PDE inhibition
may result in therapeutic effects. However, some side effects of PDE inhibitors
likely are also associated with the complexity of PDEs expression patterns across
brain areas.
3 Roles of PDEs in Mood and Cognitive Disorders
The complex functions of PDEs in cell-cell communication and signal transduction
are only recently being recognized, although PDEs were described soon after the
discovery of cAMP. A PDE gene organization with a large number of PDE splice
variants serves to fine-tune cyclic nucleotide concentrations and compartmentalization
