Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study

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 [ 11 C]Lu AE92686 was performed, followed by a 6 min restingstate 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.

Effects of chronic voluntary alcohol consumption on PDE10A availability: a longitudinal behavioural and [18F]JNJ42259152 PET study in rats

“…PDEs can promote alcohol intake through reduction of cyclic nucleotide activity [40]. Considering the limited distribution of PDE10A to the striatal GABAergic MSNs, together with the role of PDE10A in cAMP-PKA-DARPP-32 signaling cascade and metabolism in the MSNs, several studies have demonstrated a relation between abnormal striatal dopaminergic transmission characterizing neurodegenerative and neuropsychiatric basal ganglia diseases and the loss of PDE10A enzyme levels and expression [18,[21][22][23]27]. Upregulated striatal signaling, is PDE10A-regulated in processes controlling reward-motivated behaviors and furthermore, incentive salience [41].…”

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

“…In 2019, Persson et al [ 163 ] published a combined [ 11 C] 32 PET and functional MRI (fMRI) follow-up study in the same cohort of schizophrenia patients like Bodén at al. [ 161 ].…”

“…[ 161 ]. This study focused on the investigation of the effect of reduced PDE10A levels in the striatum on the neuronal and behavioral function of striatal and downstream basal ganglia regions [ 163 ]. FMRI was used to measure striatal function and activity, the latter as the amplitude of low-frequency fluctuations (ALFF) [ 163 ].…”

“…This study focused on the investigation of the effect of reduced PDE10A levels in the striatum on the neuronal and behavioral function of striatal and downstream basal ganglia regions [ 163 ]. FMRI was used to measure striatal function and activity, the latter as the amplitude of low-frequency fluctuations (ALFF) [ 163 ]. PET/fMRI scans revealed a significant correlation between decreased [ 11 C] 32 BP ND and increased ALFF exclusively in the putamen and the substantia nigra [ 163 ].…”

“…FMRI was used to measure striatal function and activity, the latter as the amplitude of low-frequency fluctuations (ALFF) [ 163 ]. PET/fMRI scans revealed a significant correlation between decreased [ 11 C] 32 BP ND and increased ALFF exclusively in the putamen and the substantia nigra [ 163 ]. These results indicate a reduced PDE10A availability and an elevated excitability in the respective brain regions, consistent with previous findings where a hyperactivity in the putamen of schizophrenia patients was observed [ 163 , 164 , 165 , 166 ].…”