High frequency oscillations play important roles in development of epileptogenesis/ictogenesis via activation of astroglial signallings

Fukuyama, Kouji; Okada, Motohiro

doi:10.1016/j.biopha.2022.112846

Cited by 9 publications

(86 citation statements)

References 59 publications

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“…In our previous study, acute artificial ripple-burst evoked stimulations (100 sets) did not affect astroglial L-glutamate release [ 51 , 53 ], whereas astroglial D-serine release was increased by acute artificial ripple-burst evoked stimulations (100 set) ( Figure 1 A). Basal astroglial D-serine release was not affected by 10 μM TAT-conjugated Gap19 (Gap19), a selective Cx43-containing hemichannel inhibitor, whereas ripple-burst evoked D-serine release was inhibited by 10 μM Gap19 ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 83%

“…Astrocytes release gliotransmitters via several systems, such as exocytosis [ 46 , 47 ], transporters [ 48 ] and hemichannels [ 49 ]. During the resting state, the astroglial hemichannel cannot release gliotransmitters due to its low opening probability, whereas depolarisation of the plasma membrane activates hemichannel activity, resulting in the release of gliotransmitter through activated astroglial hemichannels [ 27 , 50 , 51 , 52 ]. To clarify the concentration-dependent effects of QTP on physiological astroglial D-serine release, the present study determined the basal and ripple-burst (which is observed during sleep spindle burst and contributes to cognitive function) evoked astroglial D-serine release (detailed method of artificial ripple-burst evoked stimulation is described in Section 4.3 ).…”

Section: Resultsmentioning

confidence: 99%

“…Recent clinical physiology explored the impacts of high-frequency oscillations on brain function and identified that high-frequency oscillations exhibit both physiological and pathological functions in a frequency-dependent manner. Physiological high-frequency oscillation, ripple-burst (80~250Hz), which is synchronised with the sleep-spindle burst, plays important roles in cognitive function, whereas pathological fast ripple-burst (250~500 Hz) contributes to epileptic discharge and neuronal damage [ 51 , 89 ]. The results that QTP could not directly activate the astroglial hemichannel, but enhanced astroglial excitatory gliotransmitters (L-glutamate and D-serine) release through the activated hemichannel, suggest the possible pathophysiology of a delayed-onset QTP-induced seizure.…”

Section: Discussionmentioning

confidence: 99%

“…The results that QTP could not directly activate the astroglial hemichannel, but enhanced astroglial excitatory gliotransmitters (L-glutamate and D-serine) release through the activated hemichannel, suggest the possible pathophysiology of a delayed-onset QTP-induced seizure. A recent study reported that ripple burst could be involved in ictogenesis in the networks that have acquired vulnerability to epileptogenesis [ 49 , 51 ]. Considering these previous findings, this study can propose a working hypothesis regarding delayed-onset QTP-induced seizure.…”

Section: Discussionmentioning

confidence: 99%

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Dose-Dependent Biphasic Action of Quetiapine on AMPK Signalling via 5-HT7 Receptor: Exploring Pathophysiology of Clinical and Adverse Effects of Quetiapine

Okada

Fukuyama

Motomura

2022

IJMS

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Recent pharmacological studies indicated that the modulation of tripartite-synaptic transmission plays important roles in the pathophysiology of schizophrenia, mood disorders and adverse reactions. Therefore, to explore the mechanisms underlying the clinical and adverse reactions to atypical antipsychotics, the present study determined the effects of the sub-chronic administration of quetiapine (QTP: 3~30 μM) on the protein expression of 5-HT7 receptor (5-HT7R), connexin43 (Cx43), cAMP level and intracellular signalling, Akt, Erk and adenosine monophosphate-activated protein kinase (AMPK) in cultured astrocytes and the rat hypothalamus, using ultra-high-pressure liquid chromatography with mass spectrometry and capillary immunoblotting systems. QTP biphasically increased physiological ripple-burst evoked astroglial D-serine release in a concentration-dependent manner, peaking at 10 μM. QTP enhanced the astroglial signalling of Erk concentration-dependently, whereas both Akt and AMPK signalling’s were biphasically enhanced by QTP, peaking at 10 μM and 3 μM, respectively. QTP downregulated astroglial 5-HT7R in the plasma membrane concentration-dependently. Protein expression of Cx43 in astroglial cytosol and intracellular cAMP levels were decreased and increased by QTP also biphasically, peaking at 3 μM. The dose-dependent effects of QTP on the protein expression of 5-HT7R and Cx43, AMPK signalling and intracellular cAMP levels in the hypothalamus were similar to those in astrocytes. These results suggest several complicated pharmacological features of QTP. A therapeutically relevant concentration/dose of QTP activates Akt, Erk and AMPK signalling, whereas a higher concentration/dose of QTP suppresses AMPK signalling via its low-affinity 5-HT7R inverse agonistic action. Therefore, 5-HT7R inverse agonistic action probably plays important roles in the prevention of a part of adverse reactions of QTP, such as weight gain and metabolic complications.

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Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Dose-Dependent Biphasic Action of Quetiapine on AMPK Signalling via 5-HT7 Receptor: Exploring Pathophysiology of Clinical and Adverse Effects of Quetiapine

Okada

Fukuyama

Motomura

2022

IJMS

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“…After washout by ACSF, cultured astrocytes were incubated in ACSF containing the same agent of chronic exposure to target agents, with or without 100 μM CBX, at 35 °C for 120 min in CO 2 incubator. Astroglial hemichannels are not functional during the resting stage owing to their low opening probability 45 . Therefore, to determine activated hemichannel functions under physiological conditions, cultured astrocytes were electrically stimulated using ripple-burst evoked stimulation using busdrive amplifier (SEG-3104MG; Miyuki Giken, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Opposing effects of clozapine and brexpiprazole on β-aminoisobutyric acid: Pathophysiology of antipsychotics-induced weight gain

2023

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Clozapine is one of the most effective antipsychotics and has the highest risk of weight gain and metabolic complications; however, the detailed pathophysiology of its clinical action and adverse reactions remains to be clarified. Therefore, the present study determined the chronic effects of clozapine (high risk of weight gain) and brexpiprazole (relatively low risk of weight gain) on intracellular and extracellular levels of β-aminoisobutyric acid (BAIBA) enantiomers, which are endogenous activators of AMP-activated protein kinase (AMPK). L-BAIBA is the dominant BAIBA enantiomer in the rat hypothalamus and cultured astrocytes, whereas L-BAIBA accounts for only approximately 5% of the total plasma BAIBA enantiomers. L-BAIBA displayed GABAB receptor agonistic action in the extracellular space and was released through activated astroglial hemichannels, whereas in the intracellular space, L-BAIBA activated AMPK signalling. Chronic administration of the effective doses of clozapine increased intracellular and extracellular levels of L-BAIBA in the hypothalamus and cultured astrocytes, whereas that of brexpiprazole decreased them. These results suggest that enhancing hypothalamic AMPK signalling by increasing intracellular L-BAIBA levels is, at least partially, involved in the pathophysiology of clozapine-induced weight gain and metabolic complications.

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Impacts of exposure to and subsequent discontinuation of clozapine on tripartite synaptic transmission

Okada,

Fukuyama,

Motomura

2024

British J Pharmacology

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Background and PurposeClozapine is an effective antipsychotic for treatment‐resistant schizophrenia, but its discontinuation leads to discontinuation syndrome/catatonia complicated by benzodiazepine‐resistance and rhabdomyolysis.Experimental ApproachThis study determined time‐dependent effects of exposure and subsequent discontinuation of clozapine on expression of connexin43, 5‐HT receptors, intracellular L‐β‐aminoisobutyrate (L‐BAIBA) and 2nd‐messengers and signalling of AMPK, PP2A and Akt in cultured astrocytes and rat frontal cortex.Key ResultsIntracellular L‐BAIBA levels increased during clozapine exposure but immediately recovered after discontinuation. Both exposure to clozapine and L‐BAIBA increased connexin43 and signalling of AMPK/Akt time‐dependently, but reduced PP2A signalling, 5‐HT receptor expression and IP3 level. These changes recovered within 2 weeks after discontinuation, while 5‐HT receptors and IP3 transiently increased during the recovery process. L‐BAIBA activated AMPK signalling, leading to attenuated PP2A signalling. Astroglial D‐serine release was increased by clozapine exposure but continued to increase within 1 week after discontinuation via activation of IP3 receptor function.Conclusion and ImplicationsClozapine discontinuation restored PP2A signalling due to decreased L‐BAIBA, increased 5‐HT receptor expression via probably enhanced 5‐HT receptor recycling, but increased astroglial D‐serine release persisted by transiently activated IP3 receptors via transiently increased IP3 level. Decreased L‐BAIBA caused by clozapine discontinuation is, at least partially, involved in the transiently increased 5‐HT receptor and astroglial D‐serine release.

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High frequency oscillations play important roles in development of epileptogenesis/ictogenesis via activation of astroglial signallings

Cited by 9 publications

References 59 publications

Dose-Dependent Biphasic Action of Quetiapine on AMPK Signalling via 5-HT7 Receptor: Exploring Pathophysiology of Clinical and Adverse Effects of Quetiapine

Dose-Dependent Biphasic Action of Quetiapine on AMPK Signalling via 5-HT7 Receptor: Exploring Pathophysiology of Clinical and Adverse Effects of Quetiapine

Opposing effects of clozapine and brexpiprazole on β-aminoisobutyric acid: Pathophysiology of antipsychotics-induced weight gain

Impacts of exposure to and subsequent discontinuation of clozapine on tripartite synaptic transmission

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