Abstract
Type 10A phosphodiesterase (PDE10A) is highly expressed in the striatum, in striatonigral and striatopallidal medium-sized spiny neurons (MSNs), which express D1 and D2 dopamine receptors, respectively. PDE10A inhibitors have pharmacological and behavioral effects suggesting an antipsychotic profile, but the cellular bases of these effects are unclear. We analyzed the effects of PDE10A inhibition in vivo by immunohistochemistry, and imaged cAMP, cAMP-dependent protein kinase A (PKA), and cGMP signals with biosensors in mouse brain slices. PDE10A inhibition in mouse striatal slices produced a steady-state increase in intracellular cAMP concentration in D1 and D2 MSNs, demonstrating that PDE10A regulates basal cAMP levels. Surprisingly, the PKA-dependent AKAR3 phosphorylation signal was strong in D2 MSNs, whereas D1 MSNs remained unresponsive. This effect was also observed in adult mice in vivo since PDE10A inhibition increased phospho-histone H3 immunoreactivity selectively in D2 MSNs in the dorsomedial striatum. The PKA-dependent effects in D2 MSNs were prevented in brain slices and in vivo by mutation of the PKA-regulated phosphorylation site of 32 kDa dopamine- and cAMP-regulated phosphoprotein (DARPP-32), which is required for protein phosphatase-1 inhibition. These data highlight differences in the integration of the cAMP signal in D1 and D2 MSNs, resulting from stronger inhibition of protein phosphatase-1 by DARPP-32 in D2 MSNs than in D1 MSNs. This study shows that PDE10A inhibitors share with antipsychotic medications the property of activating preferentially PKA-dependent signaling in D2 MSNs.
Highlights
Schizophrenia is a devastating psychiatric disease, which results in persistent cognitive and emotional impairments
Our study shows that PDE10A is expressed and functional in all types of medium-sized spiny neurons (MSNs), its inhibition in striatal slices produces a higher protein kinase A (PKA)-dependent protein phosphorylation response in D2 MSNs than in D1 MSNs
We provide evidence that this difference is present in all striatal regions in brain slices and in the dorsomedial striatum of adult mice in vivo
Summary
Schizophrenia is a devastating psychiatric disease, which results in persistent cognitive and emotional impairments. Besides PDE10A, striatal neurons express a number of specific signaling proteins that markedly differ from those in other brain regions (Girault, 2012), and that determine the characteristics of the cAMP/PKA signaling pathway (Castro et al, 2013). Among these specific proteins, DARPP-32 (32-kDa dopamine and cAMP-regulated phosphoprotein) is a multifunctional protein regulating phosphatase and kinase activities: for example, when DARPP-32 is phosphorylated at threonine 34 residue (Thr34) by PKA, it becomes a potent inhibitor of serine/threonine protein phosphatase-1 (PP-1; Hemmings et al, 1984; Svenningsson et al, 2004), increasing the duration of PKA-dependent signals (Castro et al, 2013)
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