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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

PF-2545920 increases the excitability of pyramidal neurons in the CA1 region. (A) Representative traces of action potentials (APs), mEPSCs, mIPSCs before and after the perfusion of PF-2545920. (B) Frequency of APs increased significantly in pyramidal neurons after perfusion of PF-2545920 (data are means ± SEM, n = 10, *P < 0.05). (C) Frequency of mEPSC increased significantly after PF-2545920 perfusion (data are means ± SEM, n = 10, **P < 0.01), and its representative cumulative fractions. (D) Amplitude of mEPSC was not altered after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions. (E) Data demonstrated no significant difference in the frequency of mIPSCs after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions. (F) Data revealed no significant difference in the amplitude of mIPSC after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions.
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Figure 4: PF-2545920 increases the excitability of pyramidal neurons in the CA1 region. (A) Representative traces of action potentials (APs), mEPSCs, mIPSCs before and after the perfusion of PF-2545920. (B) Frequency of APs increased significantly in pyramidal neurons after perfusion of PF-2545920 (data are means ± SEM, n = 10, *P < 0.05). (C) Frequency of mEPSC increased significantly after PF-2545920 perfusion (data are means ± SEM, n = 10, **P < 0.01), and its representative cumulative fractions. (D) Amplitude of mEPSC was not altered after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions. (E) Data demonstrated no significant difference in the frequency of mIPSCs after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions. (F) Data revealed no significant difference in the amplitude of mIPSC after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions.

Mentions: We used whole cell patch-clamp electrophysiology on CA1 pyramidal neurons in rat hippocampal slices perfused with Mg2+-free ACSF to further evaluate the role of PF-2545920 in the hippocampus and verify observations from the behavioral tests. Figure 4A show the typical features of APs, mEPSCs, and mIPSCs, respectively, in pyramidal neurons before or after perfusion with PF-2545920 (5 μM). The frequency of APs from pyramidal neurons after PF-2545920 (5 μM) perfusion increased significantly compared with the frequency immediately prior to perfusion with Mg2+-free ACSF (Figure 4B, 4.26 ± 1.19 Hz vs. 1.86 ± 0.39 Hz; n = 10, P < 0.05). To determine whether the imbalance of excitatory and inhibitory transmission may cause neuronal hyperexcitability, we recorded mEPSCs and mIPSCs. Brain slices perfused with PF-2545920 demonstrated a significant increase in the frequency of mEPSCs (Figure 4C, 5.92 ± 1.45 Hz vs. 1.50 ± 0.64 Hz; n = 10, P < 0.05). No significant differences between groups were found in the amplitude of mEPSCs (Figure 4D) or the frequency (Figure 4E) or amplitude of mIPSCs (Figure 4F). The corresponding cumulative fraction of mEPSCs or mIPSCs confirmed our results. There was no significant difference in the frequency of AP or the frequency or amplitude of mEPSCs and mIPSCs prior to perfusion or after washout (Figure 4A, n = 10, P > 0.05). The electrophysiological data were consistent with and confirmed the findings of our animal behavior study.


The Phosphodiesterase 10A Inhibitor PF-2545920 Enhances Hippocampal Excitability and Seizure Activity Involving the Upregulation of GluA1 and NR2A in Post-synaptic Densities
PF-2545920 increases the excitability of pyramidal neurons in the CA1 region. (A) Representative traces of action potentials (APs), mEPSCs, mIPSCs before and after the perfusion of PF-2545920. (B) Frequency of APs increased significantly in pyramidal neurons after perfusion of PF-2545920 (data are means ± SEM, n = 10, *P < 0.05). (C) Frequency of mEPSC increased significantly after PF-2545920 perfusion (data are means ± SEM, n = 10, **P < 0.01), and its representative cumulative fractions. (D) Amplitude of mEPSC was not altered after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions. (E) Data demonstrated no significant difference in the frequency of mIPSCs after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions. (F) Data revealed no significant difference in the amplitude of mIPSC after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions.
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Figure 4: PF-2545920 increases the excitability of pyramidal neurons in the CA1 region. (A) Representative traces of action potentials (APs), mEPSCs, mIPSCs before and after the perfusion of PF-2545920. (B) Frequency of APs increased significantly in pyramidal neurons after perfusion of PF-2545920 (data are means ± SEM, n = 10, *P < 0.05). (C) Frequency of mEPSC increased significantly after PF-2545920 perfusion (data are means ± SEM, n = 10, **P < 0.01), and its representative cumulative fractions. (D) Amplitude of mEPSC was not altered after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions. (E) Data demonstrated no significant difference in the frequency of mIPSCs after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions. (F) Data revealed no significant difference in the amplitude of mIPSC after PF-2545920 treatment (data are means ± SEM, n = 10, P > 0.05), and its representative cumulative fractions.
Mentions: We used whole cell patch-clamp electrophysiology on CA1 pyramidal neurons in rat hippocampal slices perfused with Mg2+-free ACSF to further evaluate the role of PF-2545920 in the hippocampus and verify observations from the behavioral tests. Figure 4A show the typical features of APs, mEPSCs, and mIPSCs, respectively, in pyramidal neurons before or after perfusion with PF-2545920 (5 μM). The frequency of APs from pyramidal neurons after PF-2545920 (5 μM) perfusion increased significantly compared with the frequency immediately prior to perfusion with Mg2+-free ACSF (Figure 4B, 4.26 ± 1.19 Hz vs. 1.86 ± 0.39 Hz; n = 10, P < 0.05). To determine whether the imbalance of excitatory and inhibitory transmission may cause neuronal hyperexcitability, we recorded mEPSCs and mIPSCs. Brain slices perfused with PF-2545920 demonstrated a significant increase in the frequency of mEPSCs (Figure 4C, 5.92 ± 1.45 Hz vs. 1.50 ± 0.64 Hz; n = 10, P < 0.05). No significant differences between groups were found in the amplitude of mEPSCs (Figure 4D) or the frequency (Figure 4E) or amplitude of mIPSCs (Figure 4F). The corresponding cumulative fraction of mEPSCs or mIPSCs confirmed our results. There was no significant difference in the frequency of AP or the frequency or amplitude of mEPSCs and mIPSCs prior to perfusion or after washout (Figure 4A, n = 10, P > 0.05). The electrophysiological data were consistent with and confirmed the findings of our animal behavior study.

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