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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.


Related in: MedlinePlus

The p-GluA1Ser845/GluA1 ratio and CaMKII in rat hippocampus. (A) Representative Western blot shows that seizures significantly decreased the ratios of p-GluA1Ser845 relative to GluA1 in total homogenates. PF significantly increased the ratios of p-GluA1Ser845 relative to GluA1 in groups with SE (n = 5, *P < 0.05; ***P < 0.001). (B) Representative Western blot shows that seizures significantly decreased the expression of CaMKII in total homogenates. PF significantly decreased the expression of CaMKII in groups without SE (n = 5, *P < 0.05; **P < 0.01).
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Figure 6: The p-GluA1Ser845/GluA1 ratio and CaMKII in rat hippocampus. (A) Representative Western blot shows that seizures significantly decreased the ratios of p-GluA1Ser845 relative to GluA1 in total homogenates. PF significantly increased the ratios of p-GluA1Ser845 relative to GluA1 in groups with SE (n = 5, *P < 0.05; ***P < 0.001). (B) Representative Western blot shows that seizures significantly decreased the expression of CaMKII in total homogenates. PF significantly decreased the expression of CaMKII in groups without SE (n = 5, *P < 0.05; **P < 0.01).

Mentions: PF-2545920 affects the phosphorylation of GluA1 at Ser845 (p-GluA1Ser845) (Grauer et al., 2009). Our study demonstrated that the ratio of p-GluA1Ser845/GluA1 in PF-SE was significantly higher than the V-SE group (Figure 6A, 1.135 ± 0.126 vs. 0.679 ± 0.022; n = 5, P < 0.05). Previous studies have demonstrated that CaMKII participates in the synaptic modification of synaptic receptors (NMDARs, AMPARs). Our data revealed that PF-2545920 downregulated CaMKII expression compared with the non-SE groups (Figure 6B, 0.588 ± 0.073 vs. 0.93 ± 0.167; n = 5, P < 0.05).


The Phosphodiesterase 10A Inhibitor PF-2545920 Enhances Hippocampal Excitability and Seizure Activity Involving the Upregulation of GluA1 and NR2A in Post-synaptic Densities
The p-GluA1Ser845/GluA1 ratio and CaMKII in rat hippocampus. (A) Representative Western blot shows that seizures significantly decreased the ratios of p-GluA1Ser845 relative to GluA1 in total homogenates. PF significantly increased the ratios of p-GluA1Ser845 relative to GluA1 in groups with SE (n = 5, *P < 0.05; ***P < 0.001). (B) Representative Western blot shows that seizures significantly decreased the expression of CaMKII in total homogenates. PF significantly decreased the expression of CaMKII in groups without SE (n = 5, *P < 0.05; **P < 0.01).
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Related In: Results  -  Collection

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Figure 6: The p-GluA1Ser845/GluA1 ratio and CaMKII in rat hippocampus. (A) Representative Western blot shows that seizures significantly decreased the ratios of p-GluA1Ser845 relative to GluA1 in total homogenates. PF significantly increased the ratios of p-GluA1Ser845 relative to GluA1 in groups with SE (n = 5, *P < 0.05; ***P < 0.001). (B) Representative Western blot shows that seizures significantly decreased the expression of CaMKII in total homogenates. PF significantly decreased the expression of CaMKII in groups without SE (n = 5, *P < 0.05; **P < 0.01).
Mentions: PF-2545920 affects the phosphorylation of GluA1 at Ser845 (p-GluA1Ser845) (Grauer et al., 2009). Our study demonstrated that the ratio of p-GluA1Ser845/GluA1 in PF-SE was significantly higher than the V-SE group (Figure 6A, 1.135 ± 0.126 vs. 0.679 ± 0.022; n = 5, P < 0.05). Previous studies have demonstrated that CaMKII participates in the synaptic modification of synaptic receptors (NMDARs, AMPARs). Our data revealed that PF-2545920 downregulated CaMKII expression compared with the non-SE groups (Figure 6B, 0.588 ± 0.073 vs. 0.93 ± 0.167; n = 5, P < 0.05).

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.


Related in: MedlinePlus