Transient Blockade of ERK Phosphorylation in the Critical Period Causes Autistic Phenotypes as an Adult in Mice.

The critical period is a distinct time-window during the neonatal stage when animals display elevated sensitivity to certain environmental stimuli, and particular experiences can have profound and long-lasting effects on behaviors. Increasing evidence suggests that disruption of neuronal activity during the critical period contributes to autistic phenotype, although the pathogenic mechanism is largely unknown. Herein we show that extracellular signal-regulated protein kinases (ERKs) play important roles in proper formation of neural circuits during the critical period. Transient blockade of ERKs phosphorylation at postnatal day 6 (P6) by intraperitoneal injection of blood-brain barrier-penetrating MEK inhibitor, α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327) caused significant increase of apoptosis in the forebrain. Furthermore, this induced long-term deleterious effects on brain functioning later in adulthood, resulting in social deficits, impaired memory and reduced long-term potentiation (LTP). Conversely, blockade of ERK phosphorylation at P14 no longer induced apoptosis, nor behavioral deficits, nor the reduced LTP. Thus, surprisingly, these effects of ERKs are strongly age-dependent, indicating that phosphorylation of ERKs during the critical period is absolutely required for proper development of brain functioning. This study provides novel insight into the mechanistic basis for neurodevelopment disorders: various neurodevelopment disorders might be generally linked to defects in ERKs signaling during the critical period.

The effect of a new water-soluble sedative-hypnotic drug, JM-1232(-), on long-term potentiation in the CA1 region of the mouse hippocampus.

BACKGROUND: JM-1232(-) {(-)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta[f]isoindol-1(2H)-one} is a new water-soluble sedative-hypnotic drug with affinity for the benzodiazepine binding site on γ-aminobutyric acid A receptors. The effects of JM-1232(-) on synaptic transmission in the brain are not known. In the present study, we investigated the effects of JM-1232(-) on synaptic transmission, synaptic plasticity (i.e., long-term potentiation [LTP] and paired-pulse facilitation), and excitatory/inhibitory postsynaptic currents (EPSCs/IPSCs) of pyramidal neurons in the CA1 region of mouse hippocampal slices. METHODS: We recorded Schaffer collateral-evoked field excitatory postsynaptic potentials and EPSCs and IPSCs of pyramidal neurons using whole-cell patch-clamp techniques in the CA1 region of mouse hippocampal slices. RESULTS: JM-1232(-) had no significant effect on the field excitatory postsynaptic potentials. Application of JM-1232(-) for 20 minutes before theta-burst stimulation dose dependently impaired LTP. JM-1232(-) impaired paired-pulse facilitation. The benzodiazepine antagonist flumazenil abolished the inhibitory effect of JM-1232(-) on LTP and paired-pulse facilitation. JM-1232(-) had no effect on Schaffer collateral stimulation-evoked EPSCs, whereas it potentiated the amplitude and prolonged the decay of evoked IPSCs in CA1 pyramidal neurons. Flumazenil blocked the effect of JM-1232(-) on the amplitude and decay of evoked IPSCs. JM-1232(-) suppressed the action potential discharge in the CA1 pyramidal neurons during theta-burst stimulation, which was reversed by flumazenil. CONCLUSION: JM-1232(-) enhances synaptic inhibition and impairs LTP and paired-pulse facilitation in area CA1 of the mouse hippocampus. These effects were mediated by benzodiazepine binding sites on γ-aminobutyric acid A receptors.

Dexmedetomidine reduces long-term potentiation in mouse hippocampus.

BACKGROUND: Dexmedetomidine (Precedex; Abbott Laboratories, Abbott Park, IL) is a selective alpha2-adrenergic agonist that also has affinity for imidazoline receptors. In clinical studies, dexmedetomidine has sedative effects and impairs memory, but the action of dexmedetomidine on synaptic plasticity in the brain has yet to be established. In the present study, the authors investigated the effects of dexmedetomidine on two forms of synaptic plasticity-long-term potentiation (LTP) and paired-pulse facilitation-in the CA1 region of mouse hippocampal slices. METHODS: The authors recorded Schaffer collateral-evoked field excitatory postsynaptic potentials from mouse hippocampal slices in CA1 stratum radiatum. The slope of the rising phase of the field excitatory postsynaptic potential was used to estimate the strength of synaptic transmission. RESULTS: Application of dexmedetomidine for 20 min before "theta burst" stimulation dose-dependently attenuated LTP, and half-inhibitory concentration of dexmedetomidine was 28.6 +/- 5.7 nm. The inhibitory effect of dexmedetomidine on LTP was not abolished by an alpha2-adrenoceptor antagonist (yohimbine), an imidazoline type 1 receptor and alpha2-adrenoceptor antagonist (efaroxan), an alpha1-adrenoceptor antagonist (prazosin), or a gamma-aminobutyric acid type A receptor antagonist (picrotoxin). However, an imidazoline type 2 receptor and alpha2-adrenoceptor antagonist (idazoxan) completely blocked the dexmedetomidine-induced attenuation. Furthermore, 2-benzofuranyl-2-imidaloline, a selective imidazoline type 2 receptor ligand, reduced LTP. 2-(4,5-dihydroimidaz-2-yl)-quinoline, another imidazoline type 2 receptor ligand, abolished the 2-benzofuranyl-2-imidaloline-induced attenuation, but the inhibitory effect of dexmedetomidine on LTP was not abolished by 2-(4,5-dihydroimidaz-2-yl)-quinoline. Dexmedetomidine did not affect paired-pulse facilitation. CONCLUSION: Dexmedetomidine impairs LTP in area CA1 of the mouse hippocampus via imidazoline type 2 receptors and alpha2-adrenoceptors.

Propofol-mediated impairment of CA1 long-term potentiation in mouse hippocampal slices.

Propofol (2,6-diisopropylphenol) is a short-acting intravenous anesthetic. Propofol is known to impair maintenance of long-term potentiation (LTP) in synaptic responses from Schaffer collateral-commissural (SC) pathway to CA1 pyramidal cells in the hippocampus, but the threshold concentration of propofol needed to elicit this action is unknown. The actions of propofol in vivo (e.g., amnesia, sedation, hypnosis and immobility) depend on its concentration, and thus it is necessary to determine the concentration required to impair CA1 LTP in order to assess the impact of impairment in vivo. In the present study, we investigated the effects of various concentrations of propofol on synaptic plasticity, primarily by measuring LTP at SC pathway to CA1 pyramidal cell synapses in mouse hippocampal slices. Continuous application of 50 microM propofol from 20 min before tetanus stimulation suppressed potentiation of the synaptic responses by tetanus stimulation. The suppression was pronounced from 10 min post-tetanus and about 55% suppression of the potentiation was observed at 60 min after tetanus. Propofol at 5 or 20 microM did not have this effect. The presence of gamma-aminobutyric acid type A (GABA(A)) receptors antagonist, picrotoxin, abrogated the suppression of LTP by 50 microM propofol. Propofol 50 microM did not affect long-term depression (LTD). These results suggest that the suppression of hippocampal CA1 LTP via GABA(A) receptors requires a much higher propofol concentration compared with that needed to induce amnesia.

The Brandt tube system attenuates the cuff deflationary phenomenon after anesthesia with nitrous oxide.

The Brandt tube system can limit excessive cuff pressure during nitrous oxide (N(2)O) anesthesia, but there is a lack of data assessing whether the Brandt tube system avoids cuff deflation after cessation of N(2)O administration. In this study, we recorded air-filled cuff pressures of the Mallinckrodt Brandt or Hi-Contour (control) tracheal tubes (Mallinckrodt, Athlone, Ireland) during 67% N(2)O anesthesia and the cuffs were aspirated if the cuff pressure exceeded 22 mm Hg; 180 min later, O(2) was substituted for N(2)O. The cuff pressure of both groups significantly decreased after N(2)O anesthesia but the time required for the cuff pressure to return to the initial pressure was longer in the Brandt group than in the control group (76.5 +/- 35.2 min and 36.5 +/- 18.1 min, respectively; P = 0.03). The incidence of air leaks was more frequent in the control group than in the Brandt group (P = 0.015); changes in intracuff N(2)O were small in the Brandt group (6.6 +/- 1.2% to 3.4 +/- 0.9%) compared with those in the control group (46.2 +/- 3.8% to 18.6 +/- 5.6%). Therefore, the Brandt tube system attenuates the cuff deflationary phenomenon after N(2)O anesthesia, whereas repeated cuff deflation during N(2)O anesthesia causes cuff deflation after cessation of N(2)O, resulting in a possible risk of air leaks.

Dopamine may preserve the myocardial oxygen balance better than dobutamine when administered with milrinone.

PURPOSE: To compare the hemodynamic effects of dopamine with those of dobutamine when administered with milrinone in patients undergoing non-cardiac surgery. METHODS: In 14 patients undergoing major surgery during anesthesia with isoflurane, milrinone (50 microgram*kg(-1) followed by 0.25 microgram*kg(-1)*min(-1)) was administered. Hemodynamic baseline values were assessed 50 min after continuous infusion of milrinone. Additional infusion of either dopamine or dobutamine, randomly selected, was started at the rate of 4 and later 8 microgram*kg(-1)*min(-1); each hemodynamic variable was measured 20 min after changing the infusion rate. One hour after ceasing the infusion of one catecholamine (dopamine or dobutamine), the other was infused at the rate of 4 and 8 microgram*kg(-1)*min(-1). RESULTS: Milrinone increased heart rate (HR), but decreased mean arterial pressure (MAP) and systemic vascular resistance (SVR) (P < 0.05 for each). Dopamine administered with milrinone significantly increased MAP and cardiac output (CO), whereas dobutamine significantly increased HR and CO, but decreased SVR. By comparison between dopamine and dobutamine administered at the rate of 8 microgram*kg(-1)*min(-1), there was a significant difference in HR, MAP, and SVR (P < 0.01, 0.01, and 0.05, respectively). CONCLUSION: Dopamine and dobutamine administered with milrinone induce different hemodynamic changes: dopamine increases MAP without affecting HR, whereas dobutamine increases HR. Our data suggest that the myocardial oxygen balance might be better preserved with dopamine than with dobutamine when administered with milrinone.

Rapid deflation of the bronchial cuff of the double-lumen tube after decreasing the concentration of inspired nitrous oxide.

UNLABELLED: Deflationary phenomena of the endotracheal tube cuff may occur after inspired nitrous oxide (N(2)O) concentrations are reduced, but deflationary phenomena of the double-lumen tube (DLT) cuff have not been investigated. In this study, tracheal and bronchial cuffs of left-sided Mallinckrodt (Athlone, Ireland) DLTs were inflated with air, 40% N(2)O, or 67% N(2)O (Air, N40, or N67 groups, respectively) in 24 patients undergoing thoracic surgery; 40 min later, O(2) was substituted for N(2)O in some of the patients in the N40 group (N40-c group). Intracuff gas volumes, N(2)O concentrations, and cuff compliance were also measured. Both tracheal and bronchial cuff pressures significantly increased in the Air group but decreased in the N67 group. Neither pressure significantly changed in the N40 group, but both decreased in the N40-c group after terminating N(2)O anesthesia; the time required for bronchial cuff pressures to decrease by half (12.0 +/- 5.5 min) was less than that for tracheal cuff pressures (31.2 +/- 11.0 min, P < 0.01). The volume change in the N40-c group was not significantly different between the tracheal and bronchial cuffs, but tracheal cuff compliance was significantly higher than bronchial compliance. Therefore, filling DLT cuffs with 40% N(2)O stabilizes cuff pressure during anesthesia with 67% N(2)O, but bronchial cuffs deflate more quickly than tracheal cuffs after cessation of N(2)O administration through smaller compliance. IMPLICATIONS: We demonstrated that after cessation of nitrous oxide (N(2)O) administration, bronchial N(2)O-filled cuffs of the double-lumen tube deflate more rapidly than tracheal cuffs. To avoid insufficient separation of the lungs by the bronchial cuff, a frequent check of the cuff pressure is recommended after the inspired N(2)O concentration is decreased.