Limits...
The Phosphodiesterase 10A Inhibitor PF-2545920 Enhances Hippocampal Excitability and Seizure Activity Involving the Upregulation of GluA1 and NR2A in Post-synaptic Densities

View Article: PubMed Central - PubMed

ABSTRACT

Phosphodiesterase regulates the homeostasis of cAMP and cGMP, which increase the strength of excitatory neural circuits and/or decrease inhibitory synaptic plasticity. Abnormally, synchronized synaptic transmission in the brain leads to seizures. A phosphodiesterase 10A (PDE10A) inhibitor PF-2545920 has recently attracted attention as a potential therapy for neurological and psychiatric disorders. We hypothesized that PF-2545920 plays an important role in status epilepticus (SE) and investigated the underlying mechanisms. PDE10A was primarily located in neurons, and PDE10A expression increased significantly in patients with temporal lobe epilepsy. PF-2545920 enhanced the hyperexcitability of pyramidal neurons in rat CA1, as measured by the frequency of action potentials and miniature excitatory post-synaptic current. GluA1 and NR2A expression also increased significantly in post-synaptic densities, with or without SE in rats treated with PF-2545920. The ratio of p-GluA1/GluA1 increased in the presence of PF-2545920 in groups with SE. Our results suggest that PF-2545920 facilitates seizure activity via the intracellular redistribution of GluA1 and NR2A in the hippocampus. The upregulation of p-GluA1 may play an important role in trafficking GluA1 to post-synaptic densities. The data suggest it would be detrimental to use the drug in seizure patients and might cause neuronal hyperexcitability in non-epileptic individuals.

No MeSH data available.


PDE10A expression in the temporal cortex of TLE patients. (A) Triple-label immunofluorescence demonstrated that PDE10A (green) and GFAP (red) were not co-expressed in astrocytes, but PDE10A (green) and MAP2 (blue) were co-expressed in the neurons of patient cortex (n = 10). The white squares indicate positive cells. (B) Representative Western blots revealed PDE10A expression in TLE patients and controls. The mean OD ratio of PDE10A relative to β-actin was significantly higher in the TLE group compared with the control group (**P < 0.01).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5383654&req=5

Figure 2: PDE10A expression in the temporal cortex of TLE patients. (A) Triple-label immunofluorescence demonstrated that PDE10A (green) and GFAP (red) were not co-expressed in astrocytes, but PDE10A (green) and MAP2 (blue) were co-expressed in the neurons of patient cortex (n = 10). The white squares indicate positive cells. (B) Representative Western blots revealed PDE10A expression in TLE patients and controls. The mean OD ratio of PDE10A relative to β-actin was significantly higher in the TLE group compared with the control group (**P < 0.01).

Mentions: Data from our animal studies suggested that PDE10A is involved in the acute seizure model; therefore, we hypothesized that it may play a role in epilepsy patients. We examined PDE10A expression using Western blotting and immunofluorescence. Immunofluorescence staining demonstrated that PDE10A (green) and MAP2 (blue) are co-expressed in neurons in the neocortex of TLE patients but not with GFAP (red) in astrocytes (Figure 2A). Negative control for all channels was shown in the (Supplementary Material Figure S1). We performed Western blotting to examine alternations in PDE10A expression in human sections. PDE10A expression increased significantly in TLE patients compared with control groups (P < 0.05) (Figure 2B).


The Phosphodiesterase 10A Inhibitor PF-2545920 Enhances Hippocampal Excitability and Seizure Activity Involving the Upregulation of GluA1 and NR2A in Post-synaptic Densities
PDE10A expression in the temporal cortex of TLE patients. (A) Triple-label immunofluorescence demonstrated that PDE10A (green) and GFAP (red) were not co-expressed in astrocytes, but PDE10A (green) and MAP2 (blue) were co-expressed in the neurons of patient cortex (n = 10). The white squares indicate positive cells. (B) Representative Western blots revealed PDE10A expression in TLE patients and controls. The mean OD ratio of PDE10A relative to β-actin was significantly higher in the TLE group compared with the control group (**P < 0.01).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383654&req=5

Figure 2: PDE10A expression in the temporal cortex of TLE patients. (A) Triple-label immunofluorescence demonstrated that PDE10A (green) and GFAP (red) were not co-expressed in astrocytes, but PDE10A (green) and MAP2 (blue) were co-expressed in the neurons of patient cortex (n = 10). The white squares indicate positive cells. (B) Representative Western blots revealed PDE10A expression in TLE patients and controls. The mean OD ratio of PDE10A relative to β-actin was significantly higher in the TLE group compared with the control group (**P < 0.01).
Mentions: Data from our animal studies suggested that PDE10A is involved in the acute seizure model; therefore, we hypothesized that it may play a role in epilepsy patients. We examined PDE10A expression using Western blotting and immunofluorescence. Immunofluorescence staining demonstrated that PDE10A (green) and MAP2 (blue) are co-expressed in neurons in the neocortex of TLE patients but not with GFAP (red) in astrocytes (Figure 2A). Negative control for all channels was shown in the (Supplementary Material Figure S1). We performed Western blotting to examine alternations in PDE10A expression in human sections. PDE10A expression increased significantly in TLE patients compared with control groups (P < 0.05) (Figure 2B).

View Article: PubMed Central - PubMed

ABSTRACT

Phosphodiesterase regulates the homeostasis of cAMP and cGMP, which increase the strength of excitatory neural circuits and/or decrease inhibitory synaptic plasticity. Abnormally, synchronized synaptic transmission in the brain leads to seizures. A phosphodiesterase 10A (PDE10A) inhibitor PF-2545920 has recently attracted attention as a potential therapy for neurological and psychiatric disorders. We hypothesized that PF-2545920 plays an important role in status epilepticus (SE) and investigated the underlying mechanisms. PDE10A was primarily located in neurons, and PDE10A expression increased significantly in patients with temporal lobe epilepsy. PF-2545920 enhanced the hyperexcitability of pyramidal neurons in rat CA1, as measured by the frequency of action potentials and miniature excitatory post-synaptic current. GluA1 and NR2A expression also increased significantly in post-synaptic densities, with or without SE in rats treated with PF-2545920. The ratio of p-GluA1/GluA1 increased in the presence of PF-2545920 in groups with SE. Our results suggest that PF-2545920 facilitates seizure activity via the intracellular redistribution of GluA1 and NR2A in the hippocampus. The upregulation of p-GluA1 may play an important role in trafficking GluA1 to post-synaptic densities. The data suggest it would be detrimental to use the drug in seizure patients and might cause neuronal hyperexcitability in non-epileptic individuals.

No MeSH data available.