Phosphodiesterase 10A (PDE10A): Regulator of Dopamine Agonist-Induced Gene Expression in the Striatum

Abstract

Dopamine and other neurotransmitters have the potential to induce neuroplasticity in the striatum via gene regulation. Dopamine receptor-mediated gene regulation relies on second messenger cascades that involve cyclic nucleotides to relay signaling from the synapse to the nucleus. Phosphodiesterases (PDEs) catalyze cyclic nucleotides and thus potently control cyclic nucleotide signaling. We investigated the role of the most abundant striatal PDE, PDE10A, in striatal gene regulation by assessing the effects of PDE10A inhibition (by a selective PDE10A inhibitor, TP-10) on gene regulation and by comparing the basal expression of PDE10A mRNA throughout the striatum with gene induction by dopamine agonists in the intact or dopamine-depleted striatum. Our findings show that PDE10A expression is most abundant in the sensorimotor striatum, intermediate in the associative striatum and lower in the limbic striatum. The inhibition of PDE10A produced pronounced increases in gene expression that were directly related to levels of local PDE10A expression. Moreover, the gene expression induced by L-DOPA after dopamine depletion (by 6-OHDA), or by psychostimulants (cocaine, methylphenidate) in the intact striatum, was also positively correlated with the levels of local PDE10A expression. This relationship was found for gene markers of both D1 receptor- and D2 receptor-expressing striatal projection neurons. Collectively, these results indicate that PDE10A, a vital part of the dopamine receptor-associated second messenger machinery, is tightly linked to drug-induced gene regulation in the striatum. PDE10A may thus serve as a potential target for modifying drug-induced gene regulation and related neuroplasticity.

Oligonol ameliorates liver function and brain function in the 5 × FAD mouse model: transcriptional and cellular analysis

“…The volcano graph demonstrates the distinguishing genes of the dopamine transporter Slc6a3 gene, related to neuropsychiatric diseases, 109,110 Tph2 , related to serotonergic neuronal cell regulation, 111,112 and Gh , related to inflammation. 113 In addition, our transcriptome data showed 20 increased genes, including Cdh12 , related to the upregulation of neurite growth; 114 Apold1 , associated with angiogenesis and blood brain permeability; 115,116 Poc1a , related to the regulation of neuronal spindle function; 117 Kcnh7 , associated with the downregulation of schizophrenia; 118 Atp2b , related to the protection of γ-aminobutyric acid (GABA)ergic neurons; 119 Cnr1 , related to mood disorder and dopaminergic neurotransmission; 120,121 Camp4 , related to the upregulation of memory formation improvement; 122 Dclk3 , associated with neuroprotective function in the dentate gyrus in hippocampal formation and Huntington's disease; 123 Pde10a , related to regulation of the dopamine system in neurons; 124 Rgs4 , associated with neurotransmitter transmission, psychiatric disorders such as depression and autism, and cognition; 125–127 Cdkl5 , related to the downregulation of seizure and motor dysfunction; 128 Homer1 , related to the downregulation of epilepsy, autism, addiction, schizophrenia, and depression; 128 Hivep2 , related to the regulation of dopaminergic neurons; 129 and Syt1 , related to the regulation of neurotransmitter release 130 in the 5 × FAD mouse hippocampus after oligonol treatment.…”

“…158 Additionally, Tnik, related to cognition and postsynaptic formation; 159 Rgs7, associated with synaptic plasticity and memory formation; 160 Pde4b, related to the inhibition of memory acquisition; 161 and Pde10a, related to the secretion of dopamine by neurons. 124…”

“…158 Additionally, Tnik, related to cognition and postsynaptic formation; 159 Rgs7, associated with synaptic plasticity and memory formation; 160 Pde4b, related to the inhibition of memory acquisition; 161 and Pde10a, related to the secretion of dopamine by neurons. 124 In summary, oral oligonol administration may contribute to the activation of the antioxidant response pathway, reduce ROS generation, modulate glucose metabolism and cytokine and adipokine production, increase glial reactivity, activate synaptic plasticity and neuronal function, and increase serotonin receptor expression in AD. These consequences may lead to stable mood conditions and improved cognitive function in the AD brain.…”

PDE10A Mutation as an Emerging Cause of Childhood-Onset Hyperkinetic Movement Disorders: A Review of All Published Cases

“…PDE10A expression is most abundant in the sensorimotor striatum, intermediate in the associative striatum and lower in the limbic striatum (26). This might explain the fact that patients carrying a PDE10A mutation had mainly motor impairment without serious cognitive or behavioral symptoms.…”

“…Binding of dopamine to D1R triggers cAMP synthesis and neural excitability (2). PDEs terminate such second messenger signaling by degrading cyclic nucleotides (26). PDE10A might function as a ''brake'' for MSN activation, in case of high intracellular levels of cAMP.…”