Abstract
Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.
Highlights
Established antipsychotic treatments in schizophrenia act mainly by blocking dopamine D 2 receptors in the striatum and are generally effective in reducing positive symptoms
Correlations between amplitude of low-frequency fluctuations (ALFF) and striatal phosphodiesterase 10A (PDE10A) are summarized in Table 1, and significant correlations are illustrated in Figs. 2, 3
This study aimed to explore the relationship between striatal PDE10A levels and neural and behavioral function of striatal and downstream basal ganglia regions, in patients with schizophrenia
Summary
Established antipsychotic treatments in schizophrenia act mainly by blocking dopamine D 2 receptors in the striatum and are generally effective in reducing positive symptoms. Negative and cognitive symptoms are often refractory to antipsychotic treatment and have a deleterious impact on quality of life and social functioning [1, 2]. There is a great need for new treatments to target this broad range of symptoms. One possible treatment option is the pharmacological inhibition of phosphodiesterase 10A (PDE10A) [3,4,5]. PDE10A is an enzyme that is highly concentrated and localized in striatal medium spiny neurons (MSN) across mammalian species [6]. PDE10A regulates the excitability of MSNs mainly through the inactivation of the second
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