Abstract
Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling/neuronal plasticity/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices.
Highlights
Phosphodiesterase-4 (PDE4) inhibitors such as rolipram produce antidepressant-like[5,6] and cognition-enhancing effects[7,8,9,10] via cyclic AMP (cAMP) signaling[6,11]
Lentiviral vector-delivered shRNA caused the selective down-regulation of long-form PDE4D4 and PDE4D5 in the prefrontal cortex (PFC), consistant with previous studies[11,20,23]
The behavioral, cellular and molecular alterations induced by the chronic unpredictable stress (CUS) were attenuated or reversed by the long-form PDE4Ds knock-down in the PFC, similar to the Phosphodiesterase 4 (PDE4) inhibition by rolipram
Summary
Phosphodiesterase-4 (PDE4) inhibitors such as rolipram produce antidepressant-like[5,6] and cognition-enhancing effects[7,8,9,10] via cAMP signaling[6,11]. We have previously indicated long-form PDE4D variants, especially PDE4D4 and PDE4D5, may play important roles in the mediation of antidepressant-like and cognition-enhancing effects but appear not to cause emesis in normal mice[11,20]. There is no evidence of long-form PDE4Ds on the alterations in neuroendocrine, impaired neuronal plasticity, cellular and behavioral disturbances in response to CUS The gap between this promising pharmacotherapeutic target and the pathophysiology of depression hampers the development of PDE4D variant-selective inhibitors into novel antidepressants. We hypothesized that long-form PDE4Ds played a predominant role in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits
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