Cognitive dysfunction, including loss of core functions such as memory, learning and reasoning occurs in many psychiatric disorders, and impairs the quality of life for millions of older adults suffering from dementia. As there is no single cause, treatments vary. However the few drugs that are available, most of which boost neurotransmitter levels, are not very effective. A team led by Alexander McGirr, a resident physician at the University of British Columbia, recently provided compelling evidence that a phosphodiesterase responsible for hydrolyzing cyclic-AMP and linked to major psychiatric disorders may be a therapeutic target for cognitive disorders. They developed a mouse model with catalytically impaired phosphodiesterase-4B (PDE4B) that showed significant enhancements in behavioral tests of memory and problem solving as well as decreased contextual fear memory over longer periods of time. Their study, “Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition,” implicates PDE4B as a potential target for cognition and anxiety disorders and for pathological fear memory.
Cyclic AMP (cAMP) is a key regulator of fundamental brain functions related to learning, memory and higher cognition. For example, cAMP-dependent phosphorylation of the transcription factor CREB (cAMP response element binding protein) activates transcription of genes that mediate memory formation. The four PDE4 subtypes are thought to play non-redundant roles in the brain, and pan-PDE4 inhibitors such as Rolipram have shown some promise in improving memory in animal models of psychiatric and neurological diseases. However, pan-PDE4 inhibitors have serious side effects, and teasing out subtype-specific effects will be important for targeting the subfamily.
McGirr and his team generated mice with two copies of a catalytically impaired mutant of PDE4B (Y358C) using chemical mutagenesis and backcrossing, screening nearly 8,000 mice to identify one founder mutant progeny. All PDE4B subtypes were expressed to normal levels in the PDE4BY358C mice, and they had normal hippocampal levels of cAMP. However, they accumulated higher than normal cAMP levels when treated with forskolin (an adenyl cyclase activator), and CREB phosphorylation was elevated 1.5- to 2.5-fold in different brain regions, consistent with increased cAMP signaling.
The behavior of the PDE4BY358C mice was strikingly different than wild type controls. They had lower levels of anxiety (including a decreased response to cat odor) and preconditioned fear, were more willing to explore, and performed better on learning and memory tests. The authors pointed out that exploratory tendencies are predictive of general cognitive abilities, and it is known that making exploration less intimidating can facilitate learning. They speculated that the PDE4BY358C mutation might cause dissociation between fear and memory formation, resulting in improved cognition. Preconditioned PDE4BY358C mice also showed higher levels of hippocampal neurogenesis, which has been linked with destabilization of contextual fear memory.
The behavioral effects of the PDE4BY358C mutation are consistent with synaptic changes favoring long-term potentiation. This was confirmed in hippocampal slices: long-term potentiation was increased and depotentiation was decreased in tissue from the mutant mice compared with wild type.
Interestingly, the PDE4BY358C mutation causes a fairly mild impairment of function—in vitro catalytic activity was decreased 27% relative to wild-type—yet the effects on cAMP signaling pathways were moderate and the changes in behavior were quite pronounced. Moreover, complete elimination of PDE4B in knockout mice has very different behavioral effects, increasing anxiety rather than decreasing it. These observations reflect the delicate balance in the control of second messenger signaling in the brain, and they point to both challenges and opportunities for developing drugs targeting PDE4B in cognitive disorders.
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