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1.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540803

RESUMEN

Distinct from ovarian estradiol, the steroid hormone 17ß-estradiol (E2) is produced in the brain and is involved in numerous functions, particularly acting as a neurosteroid. However, the physiological role of E2 and the mechanism of its effects are not well known. In hippocampal slices, 17ß-estradiol has been found to cause a modest increase in fast glutamatergic transmission; because some of these effects are rapid and acute, they might be mediated by membrane-associated receptors via nongenomic action. Moreover, activation of membrane estrogen receptors can rapidly modulate neuron function in a sex-specific manner. To further investigate the neurological role of E2, we examined the effect of E2, as an estrogen receptor (ER) agonist, on synaptic transmission in slices of the prefrontal cortex (PFC) and hippocampus in both male and female mice. Whole-cell recordings of spontaneous excitatory postsynaptic currents (sEPSC) in the PFC showed that E2 acts as a neuromodulator in glutamatergic transmission in the PFC in both sexes, but often in a cell-specific manner. The sEPSC amplitude and/or frequency responded to E2 in three ways, namely by significantly increasing, decreasing or having no response. Additional experiments using an agonist selective for ERß, diarylpropionitrile (DPN) showed that in males the sEPSC and spontaneous inhibitory postsynaptic currents sIPSC responses were similar to their E2 responses, but in females the estrogen receptor ß (ERß) agonist DPN did not influence excitatory transmission in the PFC. In contrast, in the hippocampus of both sexes E2 potentiated the gluatmatergic synaptic transmission in a subset of hippocampal cells. These data indicate that activation of E2 targeting probably a estrogen subtypes or different downstream signaling affect synaptic transmission in the brain PFC and hippocampus between males versus females mice.


Asunto(s)
Estradiol/farmacología , Receptor alfa de Estrógeno/fisiología , Hipocampo/metabolismo , Corteza Prefrontal/metabolismo , Transmisión Sináptica/fisiología , Animales , Receptor alfa de Estrógeno/agonistas , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , GABAérgicos/farmacología , Hipocampo/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Nitrilos/farmacología , Técnicas de Placa-Clamp , Corteza Prefrontal/efectos de los fármacos , Propionatos/farmacología , Caracteres Sexuales , Transmisión Sináptica/efectos de los fármacos
2.
Int J Mol Sci ; 22(1)2021 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-33401784

RESUMEN

Sensory primary afferent fibers, conveying touch, pain, itch, and proprioception, synapse onto spinal cord dorsal horn neurons. Primary afferent central terminals express a wide variety of receptors that modulate glutamate and peptide release. Regulation of the amount and timing of neurotransmitter release critically affects the integration of postsynaptic responses and the coding of sensory information. The role of GABA (γ-aminobutyric acid) receptors expressed on afferent central terminals is particularly important in sensory processing, both in physiological conditions and in sensitized states induced by chronic pain. During the last decade, techniques of opto- and chemogenetic stimulation and neuronal selective labeling have provided interesting insights on this topic. This review focused on the recent advances about the modulatory effects of presynaptic GABAergic receptors in spinal cord dorsal horn and the neural circuits involved in these mechanisms.


Asunto(s)
Neuronas GABAérgicas/metabolismo , Neuronas Aferentes/metabolismo , Dolor/metabolismo , Receptores de GABA/metabolismo , Asta Dorsal de la Médula Espinal/fisiología , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Astrocitos/metabolismo , Antagonistas del GABA/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Fibras Nerviosas/metabolismo , Fibras Nerviosas/fisiología , Dolor/fisiopatología , Transmisión Sináptica/efectos de los fármacos
3.
Adv Exp Med Biol ; 1264: 15-28, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33332001

RESUMEN

Most of our current understanding of the neuromolecular mechanisms of Cannabis action focusses on two plant cannabinoids, THC and CBD. THC acts primarily through presynaptic CB cannabinoid receptors to regulate neurotransmitter release in the brain, spinal cord and peripheral nerves. CBD action, on the other hand, is probably mediated through multiple molecular targets.


Asunto(s)
Cannabinoides/farmacología , Cannabis/química , Transmisión Sináptica/efectos de los fármacos , Cannabidiol/farmacología , Dronabinol/farmacología , Humanos , Neurotransmisores/metabolismo , Receptores de Cannabinoides/metabolismo
4.
Anesthesiology ; 134(1): 88-102, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33166389

RESUMEN

BACKGROUND: Although the widely used single L-enantiomers of local anesthetics have less toxic effects on the cardiovascular and central nervous systems, the mechanisms mediating their antinociceptive actions are not well understood. The authors hypothesized that significant differences in the ion channel blocking abilities of the enantiomers of bupivacaine would be identified. METHODS: The authors performed electrophysiologic analysis on rat dorsal root ganglion neurons in vitro and on spinal transmissions in vivo. RESULTS: In the dorsal root ganglion, these anesthetics decreased the amplitudes of action potentials. The half-maximum inhibitory concentrations of D-enantiomer D-bupivacaine were almost equal for Aß (29.5 µM), Aδ (29.7µM), and C (29.8 µM) neurons. However, the half-maximum inhibitory concentrations of L-bupivacaine was lower for Aδ (19.35 µM) and C (19.5 µM) neurons than for A ß (79.4 µM) neurons. Moreover, D-bupivacaine almost equally inhibited tetrodotoxin-resistant (mean ± SD: 15.8 ± 10.9% of the control, n = 14, P < 0.001) and tetrodotoxin-sensitive (15.4 ± 15.6% of the control, n = 11, P = 0.004) sodium currents. In contrast, L-bupivacaine suppressed tetrodotoxin-resistant sodium currents (26.1 ± 19.5% of the control, n = 18, P < 0.001) but not tetrodotoxin-sensitive sodium currents (74.5 ± 18.2% of the control, n = 11, P = 0.477). In the spinal dorsal horn, L-bupivacaine decreased the area of pinch-evoked excitatory postsynaptic currents (39.4 ± 11.3% of the control, n = 7, P < 0.001) but not touch-evoked responses (84.2 ± 14.5% of the control, n = 6, P = 0.826). In contrast, D-bupivacaine equally decreased pinch- and touch-evoked responses (38.8 ± 9.5% of the control, n = 6, P = 0.001, 42.9 ± 11.8% of the control, n = 6, P = 0.013, respectively). CONCLUSIONS: These results suggest that the L-enantiomer of bupivacaine (L-bupivacaine) effectively inhibits noxious transmission to the spinal dorsal horn by blocking action potential conduction through C and Aδ afferent fibers.


Asunto(s)
Anestésicos Locales/farmacología , Bupivacaína/farmacología , Neuronas/efectos de los fármacos , Nocicepción/efectos de los fármacos , Nervios Periféricos/efectos de los fármacos , Células del Asta Posterior/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Masculino , Fibras Nerviosas Mielínicas/efectos de los fármacos , Fibras Nerviosas Amielínicas/efectos de los fármacos , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Canales de Sodio/efectos de los fármacos , Estereoisomerismo , Tetrodotoxina/farmacología
5.
Anesthesiology ; 134(2): 219-233, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33332534

RESUMEN

BACKGROUND: The general anesthetic propofol induces frontal alpha rhythm in the cerebral cortex at a dose sufficient to induce loss of consciousness. The authors hypothesized that propofol-induced facilitation of unitary inhibitory postsynaptic currents would result in firing synchrony among postsynaptic pyramidal neurons that receive inhibition from the same presynaptic inhibitory fast-spiking neurons. METHODS: Multiple whole cell patch clamp recordings were performed from one fast-spiking neuron and two or three pyramidal neurons with at least two inhibitory connections in rat insular cortical slices. The authors examined how inhibitory inputs from a presynaptic fast-spiking neuron modulate the timing of spontaneous repetitive spike firing among pyramidal neurons before and during 10 µM propofol application. RESULTS: Responding to activation of a fast-spiking neuron with 150-ms intervals, pyramidal cell pairs that received common inhibitory inputs from the presynaptic fast-spiking neuron showed propofol-dependent decreases in average distance from the line of identity, which evaluates the coefficient of variation in spike timing among pyramidal neurons: average distance from the line of identity just after the first activation of fast-spiking neuron was 29.2 ± 24.1 (mean ± SD, absolute value) in control and 19.7 ± 19.2 during propofol application (P < 0.001). Propofol did not change average distance from the line of identity without activating fast-spiking neurons and in pyramidal neuron pairs without common inhibitory inputs from presynaptic fast-spiking neurons. The synchronization index, which reflects the degree of spike synchronization among pyramidal neurons, was increased by propofol from 1.4 ± 0.5 to 2.3 ± 1.5 (absolute value, P = 0.004) and from 1.5 ± 0.5 to 2.2 ± 1.0 (P = 0.030) when a presynaptic fast-spiking neuron was activated at 6.7 and 10 Hz, respectively, but not at 1, 4, and 13.3 Hz. CONCLUSIONS: These results suggest that propofol facilitates pyramidal neuron firing synchrony by enhancing inhibitory inputs from fast-spiking neurons. This synchrony of pyramidal neurons may contribute to the alpha rhythm associated with propofol-induced loss of consciousness.


Asunto(s)
Corteza Cerebral/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Interneuronas/efectos de los fármacos , Propofol/farmacología , Células Piramidales/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Femenino , Masculino , Modelos Animales , Ratas , Ratas Transgénicas , Sinapsis/efectos de los fármacos
6.
Nature ; 590(7845): 315-319, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33328636

RESUMEN

Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4-6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1-4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.


Asunto(s)
Antidepresivos/farmacología , Factor 4E Eucariótico de Iniciación/metabolismo , Ketamina/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Factores Eucarióticos de Iniciación/genética , Factores Eucarióticos de Iniciación/metabolismo , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Interneuronas/efectos de los fármacos , Interneuronas/metabolismo , Ketamina/análogos & derivados , Ketamina/metabolismo , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Mutación , Inhibición Neural/efectos de los fármacos , Inhibición Neural/genética , Neuronas/clasificación , Neuronas/citología , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Transmisión Sináptica/efectos de los fármacos
7.
Proc Natl Acad Sci U S A ; 117(52): 33235-33245, 2020 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-33318193

RESUMEN

The antimalarial artemisinins have also been implicated in the regulation of various cellular pathways including immunomodulation of cancers and regulation of pancreatic cell signaling in mammals. Despite their widespread application, the cellular specificities and molecular mechanisms of target recognition by artemisinins remain poorly characterized. We recently demonstrated how these drugs modulate inhibitory postsynaptic signaling by direct binding to the postsynaptic scaffolding protein gephyrin. Here, we report the crystal structure of the central metabolic enzyme pyridoxal kinase (PDXK), which catalyzes the production of the active form of vitamin B6 (also known as pyridoxal 5'-phosphate [PLP]), in complex with artesunate at 2.4-Šresolution. Partially overlapping binding of artemisinins with the substrate pyridoxal inhibits PLP biosynthesis as demonstrated by kinetic measurements. Electrophysiological recordings from hippocampal slices and activity measurements of glutamic acid decarboxylase (GAD), a PLP-dependent enzyme synthesizing the neurotransmitter γ-aminobutyric acid (GABA), define how artemisinins also interfere presynaptically with GABAergic signaling. Our data provide a comprehensive picture of artemisinin-induced effects on inhibitory signaling in the brain.


Asunto(s)
Artemisininas/farmacología , Regulación hacia Abajo , Inhibición Neural/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Piridoxal Quinasa/antagonistas & inhibidores , Transmisión Sináptica/efectos de los fármacos , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/metabolismo , Animales , Artemisininas/química , Sitios de Unión , Regulación hacia Abajo/efectos de los fármacos , Fenómenos Electrofisiológicos/efectos de los fármacos , Femenino , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Glutamato Descarboxilasa/metabolismo , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Piridoxal Quinasa/química , Piridoxal Quinasa/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Ácido gamma-Aminobutírico/biosíntesis
8.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-33321734

RESUMEN

Neurosteroids are a family of compounds that are synthesized in principal excitatory neurons and glial cells, and derive from the transformation of cholesterol into pregnenolone. The most studied neurosteroids-allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC)-are known to modulate GABAA receptor-mediated transmission, thus playing a role in controlling neuronal network excitability. Given the role of GABAA signaling in epileptic disorders, neurosteroids have profound effects on seizure generation and play a role in the development of chronic epileptic conditions (i.e., epileptogenesis). We review here studies showing the effects induced by neurosteroids on epileptiform synchronization in in vitro brain slices, on epileptic activity in in vivo models, i.e., in animals that were made epileptic with chemoconvulsant treatment, and in epileptic patients. These studies reveal that neurosteroids can modulate ictogenesis and the occurrence of pathological network activity such as interictal spikes and high-frequency oscillations (80-500 Hz). Moreover, they can delay the onset of spontaneous seizures in animal models of mesial temporal lobe epilepsy. Overall, this evidence suggests that neurosteroids represent a new target for the treatment of focal epileptic disorders.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia del Lóbulo Temporal/fisiopatología , Neuroesteroides/uso terapéutico , Animales , Anticonvulsivantes/farmacología , Ondas Encefálicas/efectos de los fármacos , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/metabolismo , Humanos , Neuroesteroides/farmacología , Transmisión Sináptica/efectos de los fármacos
9.
Mol Pharmacol ; 98(3): 203-210, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32606205

RESUMEN

Ketamine, a dissociative anesthetic, is experiencing a clinical resurgence as a fast-acting antidepressant. In the central nervous system, ketamine acts primarily by blocking NMDA receptor currents. Although it is generally safe in a clinical setting, it can be addictive, and several of its derivatives are being investigated as preferable alternatives. 2R,6R-Hydroxynorketamine (HNK), a ketamine metabolite, reproduces some of the therapeutic effects of ketamine and appears to lack abuse liability. Here, we report a systematic investigation of the effects of HNK on macroscopic responses elicited from recombinant NMDA receptors expressed in human embryonic kidney 293 cells. We found that, like ketamine, HNK reduced NMDA receptor currents in a dose-, pH-, and voltage-dependent manner. Relative to ketamine, it had 100-fold-lower potency (46 µM at pH 7.2), 10-fold-slower inhibition onset, slower apparent dissociation rate, weaker voltage dependence, and complete competition by magnesium. Notably, HNK inhibition was fully effective when applied to resting receptors. These results revealed unexpected properties of hydroxynorketamine that warrant its further investigation as a possible therapeutic in pathologies associated with NMDA receptor dysfunction. SIGNIFICANCE STATEMENT: NMDA receptors are excitatory ion channels with fundamental roles in synaptic transmission and plasticity, and their dysfunction associates with severe neuropsychiatric disorders. 2R,6R-Hydroxynorketamine, a metabolite of ketamine, mimics some of the neuroactive properties of ketamine and may lack its abuse liability. Results show that 2R,6R-hydroxynorketamine blocks NMDA receptor currents with low affinity and weak voltage dependence and is effective when applied to resting receptors. These properties highlight its effectiveness to a subset of NMDA receptor responses and recommend it for further investigation.


Asunto(s)
Antidepresivos/farmacología , Ciclohexanos/farmacología , Ketamina/análogos & derivados , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Antidepresivos/química , Ciclohexanos/química , Células HEK293 , Humanos , Concentración de Iones de Hidrógeno , Ratas , Proteínas Recombinantes/metabolismo , Transmisión Sináptica/efectos de los fármacos
10.
Am J Respir Cell Mol Biol ; 63(4): 502-509, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32603263

RESUMEN

Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a µ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity hypoventilate during sleep and develop obstructive sleep apnea, which can be treated with intranasal leptin. We hypothesized that intranasal leptin reverses opioid-induced sleep-disordered breathing in obese mice without decreasing analgesia. To test this hypothesis, mice with diet-induced obesity were treated with morphine at 10 mg/kg subcutaneously and with leptin or placebo intranasally. Sleep and breathing were recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Excitatory postsynaptic currents were recorded in vitro from hypoglossal motor neurons after the application of the µ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin and leptin. Morphine dramatically increased the frequency of apneas and greatly increased the severity of hypoventilation and obstructive sleep apnea. Leptin decreased the frequency of apneas, improved obstructive sleep apnea, and completely reversed hypoventilation, whereas morphine analgesia was enhanced. Our in vitro studies demonstrated that [D-Ala2, N-MePhe4, Gly-ol]-enkephalin reduced the frequency of excitatory postsynaptic currents in hypoglossal motoneurons and that application of leptin restored excitatory synaptic neurotransmission. Our findings suggest that intranasal leptin may prevent opioid respiratory depression during sleep in patients with obesity receiving opioids without reducing analgesia.


Asunto(s)
Analgésicos Opioides/efectos adversos , Leptina/administración & dosificación , Respiración/efectos de los fármacos , Síndromes de la Apnea del Sueño/inducido químicamente , Síndromes de la Apnea del Sueño/prevención & control , Sueño/efectos de los fármacos , Administración Intranasal/métodos , Analgesia/métodos , Animales , Modelos Animales de Enfermedad , Encefalinas/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Morfina/farmacología , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/metabolismo , Receptores Opioides mu/metabolismo , Síndromes de la Apnea del Sueño/metabolismo , Transmisión Sináptica/efectos de los fármacos
11.
Adv Pharmacol ; 89: 3-41, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32616211

RESUMEN

A single sub-anesthetic intravascular dose of the use-dependent NMDAR antagonist, ketamine, improves mood in patients with treatment resistant depression within hours that can last for days, creating an entirely new treatment strategy for the most seriously ill patients. However, the psychomimetic effects and abuse potential of ketamine require that new therapies be developed that maintain the rapid antidepressant effects of ketamine without the unwanted side effects. This necessitates a detailed understanding of what cellular and synaptic mechanisms are immediately activated once ketamine reaches the brain that triggers the needed changes to elicit the improved behavior. Intense research has centered on the effects of ketamine, and the other rapidly acting antidepressants, on excitatory and inhibitory circuits in hippocampus and medial prefrontal cortex to determine common mechanisms, including key modifications in synaptic transmission and the precise location of the NMDARs that mediate the rapid and sustained antidepressant response. We review data comparing the effects of ketamine with other NMDAR receptor modulators and the muscarinic M1 acetylcholine receptor antagonist, scopolamine, together with evidence supporting the disinhibition hypothesis and the direct inhibition hypothesis of ketamine's mechanism of action on synaptic circuits using preclinical models.


Asunto(s)
Antidepresivos/farmacología , Hipocampo/fisiología , Ketamina/farmacología , Inhibición Neural/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Hipocampo/efectos de los fármacos , Humanos , Ketamina/administración & dosificación , Ketamina/uso terapéutico , Caracteres Sexuales
12.
PLoS One ; 15(7): e0236363, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32706815

RESUMEN

Auditory steady-state responses (ASSRs) are states in which the electrical activity of the brain reacts steadily to repeated auditory stimuli. They are known to be useful for testing the functional integrity of neural circuits in the cortex, as well as for their capacity to generate synchronous activity in both human and animal models. Furthermore, abnormal gamma oscillations on ASSR are typically observed in patients with schizophrenia (SZ). Changes in neural synchrony may reflect aberrations in cortical gamma-aminobutyric acid (GABA) neurotransmission. However, GABA's impact and effects related to ASSR are still unclear. Here, we examined the effect of a GABAa receptor antagonist, (+)-bicuculline, on ASSR in free-moving rats. (+)-Bicuculline (1, 2 and 4 mg/kg, sc) markedly and dose-dependently reduced ASSR signals, consistent with current hypotheses. In particular, (+)-bicuculline significantly reduced event-related spectral perturbations (ERSPs) at 2 and 4 mg/kg between 10 and 30 minutes post-dose. Further, bicuculline (2 and 4 mg/kg) significantly and dose-dependently increased baseline gamma power. Furthermore, the occurrence of convulsions was consistent with the drug's pharmacokinetics. For example, high doses of (+)-bicuculline such as those greater than 880 ng/g in the brain induced convulsion. Additionally, time-dependent changes in ERSP with (+)-bicuculline were observed in accordance with drug concentration. This study partially unraveled the contribution of GABAa receptor signals to the generation of ASSR.


Asunto(s)
Corteza Auditiva/efectos de los fármacos , Bicuculina/administración & dosificación , Convulsivantes/administración & dosificación , Potenciales Evocados Auditivos/efectos de los fármacos , Antagonistas de Receptores de GABA-A/administración & dosificación , Transmisión Sináptica/efectos de los fármacos , Animales , Bicuculina/farmacocinética , Convulsivantes/farmacocinética , Antagonistas de Receptores de GABA-A/farmacocinética , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/metabolismo , Esquizofrenia/fisiopatología
13.
Neuron ; 107(1): 52-64.e7, 2020 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-32362337

RESUMEN

At neuronal synapses, synaptotagmin-1 (syt1) acts as a Ca2+ sensor that synchronizes neurotransmitter release with Ca2+ influx during action potential firing. Heterozygous missense mutations in syt1 have recently been associated with a severe but heterogeneous developmental syndrome, termed syt1-associated neurodevelopmental disorder. Well-defined pathogenic mechanisms, and the basis for phenotypic heterogeneity in this disorder, remain unknown. Here, we report the clinical, physiological, and biophysical characterization of three syt1 mutations from human patients. Synaptic transmission was impaired in neurons expressing mutant variants, which demonstrated potent, graded dominant-negative effects. Biophysical interrogation of the mutant variants revealed novel mechanistic features concerning the cooperative action, and functional specialization, of the tandem Ca2+-sensing domains of syt1. These mechanistic studies led to the discovery that a clinically approved K+ channel antagonist is able to rescue the dominant-negative heterozygous phenotype. Our results establish a molecular cause, basis for phenotypic heterogeneity, and potential treatment approach for syt1-associated neurodevelopmental disorder.


Asunto(s)
Trastornos del Neurodesarrollo/genética , Neuronas/fisiología , Transmisión Sináptica/genética , Sinaptotagmina I/genética , 4-Aminopiridina/farmacología , Animales , Células Cultivadas , Humanos , Ratones , Trastornos del Neurodesarrollo/fisiopatología , Neuronas/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Transmisión Sináptica/efectos de los fármacos , Sinaptotagmina I/química
14.
J Pharmacol Exp Ther ; 374(1): 126-133, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32358047

RESUMEN

The novel small-molecule psychomotor stabilizer, IRL790, is currently in clinical trial for treatment of levodopa-induced dyskinesia and psychosis in patients with Parkinson disease. Here, we used naïve mice to investigate the effects of acute systemic administration of IRL790 on protein levels and phosphorylation states of proteins relevant for synaptic plasticity and transmission. IRL790 increased pro-brain-derived neurotrophic factor protein levels and phosphorylation at Ser1303 of the N-methyl-D-aspartate (NMDA) subtype 2B glutamate receptor (NR2B) in prefrontal cortex. IRL790 also increased the phosphorylation states at Ser19, Ser31, and Ser40, respectively, of tyrosine hydroxylase in striatum. IRL790 reduced protein levels of the NR2B receptor in striatum but not in prefrontal cortex. Taken together, we report that systemically administered IRL790 rapidly elicits changes in protein level and phosphorylation state of proteins associated with a beneficial effect on synaptic markers and neurotransmission. SIGNIFICANCE STATEMENT: The novel small-molecule psychomotor stabilizer, IRL790, is currently in clinical trial for treatment of levodopa-induced dyskinesia and psychosis in patients with Parkinson disease. In this study, we report that systemically administered IRL790 rapidly elicits changes in protein level and phosphorylation state of proteins associated with a beneficial effect on synaptic markers and neurotransmission.


Asunto(s)
Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Transmisión Sináptica/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Dopamina/biosíntesis , Relación Dosis-Respuesta a Droga , Ácido Glutámico/metabolismo , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Corteza Prefrontal/citología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos
15.
J Neurosci ; 40(25): 4881-4887, 2020 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-32430298

RESUMEN

Understanding how disruption of prefrontal cortex (PFC) maturation during adolescence is crucial to reveal which neural processes could contribute to the onset of psychiatric disorders that display frontal cortical deficits. Of particular interest is the gain of GABAergic function in the PFC during adolescence and its susceptibility to the impact of transient blockade of NMDA receptor function. Here we assessed whether exposure to MK-801 during adolescence in male rats triggers a state of excitatory-inhibitory imbalance in the PFC that limits its functional capacity to regulate behavior in adulthood. Recordings from PFC brain slices revealed that MK-801 exposure during adolescence preferentially reduces the presynaptic functionality of GABAergic activity over that of excitatory synapses. As a result, an imbalance of excitatory-inhibitory synaptic activity emerges in the PFC that correlates linearly with the GABAergic deficit. Notably, the data also suggest that the diminished prefrontal GABAergic function could arise from a deficit in the recruitment of fast-spiking interneurons by excitatory inputs during adolescence. At the behavioral level, MK-801 exposure during adolescence did not disrupt the acquisition of trace fear conditioning, but markedly increased the level of freezing response during extinction testing. Infusion of the GABAA receptor-positive allosteric modulator Indiplon into the PFC before extinction testing reduced the level of freezing response in MK-801-treated rats to control levels. Collectively, the results indicate NMDA receptor signaling during adolescence enables the gain of prefrontal GABAergic function, which is required for maintaining proper excitatory-inhibitory balance in the PFC and its control of behavioral responses.SIGNIFICANCE STATEMENT A developmental disruption of prefrontal cortex maturation has been implicated in the pathophysiology of cognitive deficits in psychiatric disorders. Of particular interest is the susceptibility of the local GABAergic circuit to the impact of transient disruption of NMDA receptors. Here we found that NMDA receptor signaling is critical to enable the gain of prefrontal GABAergic transmission during adolescence for maintaining proper levels of excitatory-inhibitory balance in the PFC and its control of behavior.


Asunto(s)
Miedo/fisiología , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica/fisiología , Animales , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Extinción Psicológica/fisiología , Miedo/efectos de los fármacos , Interneuronas/efectos de los fármacos , Interneuronas/metabolismo , Masculino , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/efectos de los fármacos
16.
J Neurosci ; 40(27): 5161-5176, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32444385

RESUMEN

Alterations of excitatory synaptic function are the strongest correlate to the pathologic disturbance of cognitive ability observed in the early stages of Alzheimer's disease (AD). This pathologic feature is driven by amyloid-ß oligomers (Aßos) and propagates from neuron to neuron. Here, we investigated the mechanism by which Aßos affect the function of synapses and how these alterations propagate to surrounding healthy neurons. We used complementary techniques ranging from electrophysiological recordings and molecular biology to confocal microscopy in primary cortical cultures, and from acute hippocampal and cortical slices from male wild-type and amyloid precursor protein (APP) knock-out (KO) mice to assess the effects of Aßos on glutamatergic transmission, synaptic plasticity, and dendritic spine structure. We showed that extracellular application of Aßos reduced glutamatergic synaptic transmission and long-term potentiation. These alterations were not observed in APP KO neurons, suggesting that APP expression is required. We demonstrated that Aßos/APP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced Aßos. Intracellular Aßos participate in synaptic dysfunctions as shown by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against Aßos. Furthermore, we provide evidence that following APP processing, extracellular release of Aßos mediates the propagation of the synaptic pathology characterized by a decreased spine density of neighboring healthy neurons in an APP-dependent manner. Together, our data unveil a complementary role for Aßos in AD, while intracellular Aßos alter synaptic function, extracellular Aßos promote a vicious cycle that propagates synaptic pathology from diseased to healthy neurons.SIGNIFICANCE STATEMENT Here we provide the proof that a vicious cycle between extracellular and intracellular pools of Aß oligomers (Aßos) is required for the spreading of Alzheimer's disease (AD) pathology. We showed that extracellular Aßos propagate excitatory synaptic alterations by promoting amyloid precursor protein (APP) processing. Our results also suggest that subsequent to APP cleavage two pools of Aßos are produced. One pool accumulates inside the cytosol, inducing the loss of synaptic plasticity potential. The other pool is released into the extracellular space and contributes to the propagation of the pathology from diseased to healthy neurons. Pharmacological strategies targeting the proteolytic cleavage of APP disrupt the relationship between extracellular and intracellular Aß, providing a therapeutic approach for the disease.


Asunto(s)
Péptidos beta-Amiloides/farmacología , Precursor de Proteína beta-Amiloide/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Neuronas/metabolismo , Sinapsis/efectos de los fármacos , Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Animales , Anticuerpos Bloqueadores/farmacología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Histidina/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Cultivo Primario de Células , Transmisión Sináptica/efectos de los fármacos
17.
J Neurosci ; 40(21): 4103-4115, 2020 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-32327530

RESUMEN

Volatile anesthetics are widely used for surgery, but neuronal mechanisms of anesthesia remain unidentified. At the calyx of Held in brainstem slices from rats of either sex, isoflurane at clinical doses attenuated EPSCs by decreasing the release probability and the number of readily releasable vesicles. In presynaptic recordings of Ca2+ currents and exocytic capacitance changes, isoflurane attenuated exocytosis by inhibiting Ca2+ currents evoked by a short presynaptic depolarization, whereas it inhibited exocytosis evoked by a prolonged depolarization via directly blocking exocytic machinery downstream of Ca2+ influx. Since the length of presynaptic depolarization can simulate the frequency of synaptic inputs, isoflurane anesthesia is likely mediated by distinct dual mechanisms, depending on input frequencies. In simultaneous presynaptic and postsynaptic action potential recordings, isoflurane impaired the fidelity of repetitive spike transmission, more strongly at higher frequencies. Furthermore, in the cerebrum of adult mice, isoflurane inhibited monosynaptic corticocortical spike transmission, preferentially at a higher frequency. We conclude that dual presynaptic mechanisms operate for the anesthetic action of isoflurane, of which direct inhibition of exocytic machinery plays a low-pass filtering role in spike transmission at central excitatory synapses.SIGNIFICANCE STATEMENT Synaptic mechanisms of general anesthesia remain unidentified. In rat brainstem slices, isoflurane inhibits excitatory transmitter release by blocking presynaptic Ca2+ channels and exocytic machinery, with the latter mechanism predominating in its inhibitory effect on high-frequency transmission. Both in slice and in vivo, isoflurane preferentially inhibits spike transmission induced by high-frequency presynaptic inputs. This low-pass filtering action of isoflurane likely plays a significant role in general anesthesia.


Asunto(s)
Anestésicos por Inhalación/administración & dosificación , Tronco Encefálico/efectos de los fármacos , Isoflurano/administración & dosificación , Neuronas/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Exocitosis/efectos de los fármacos , Femenino , Masculino , Ratones , Técnicas de Placa-Clamp , Ratas , Ratas Wistar
18.
Nat Commun ; 11(1): 1466, 2020 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-32193428

RESUMEN

The positive or negative value (valence) of past experiences is normally integrated into neuronal circuits that encode episodic memories and plays an important role in guiding behavior. Here, we show, using mouse behavioral models, that glutamatergic afferents from the ventral tegmental area to the dorsal hippocampus (VTA→DH) signal negative valence to memory circuits, leading to the formation of fear-inducing context memories and to context-specific reinstatement of fear. To a lesser extent, these projections also contributed to opioid-induced place preference, suggesting a role in signaling positive valence as well, and thus a lack of dedicated polarity. Manipulations of VTA terminal activity were more effective in females and paralleled by sex differences in glutamatergic signaling. By prioritizing retrieval of negative and positive over neutral memories, the VTA→DH circuit can facilitate the selection of adaptive behaviors when current and past experiences are valence congruent.


Asunto(s)
Hipocampo/fisiología , Memoria/fisiología , Red Nerviosa/fisiología , Área Tegmental Ventral/fisiología , Animales , Condicionamiento Clásico , Giro Dentado/efectos de los fármacos , Giro Dentado/fisiología , Miedo/fisiología , Femenino , Silenciador del Gen/efectos de los fármacos , Glutamato Descarboxilasa/metabolismo , Glutamatos/metabolismo , Hipocampo/efectos de los fármacos , Cinética , Masculino , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , Morfina/farmacología , Red Nerviosa/efectos de los fármacos , Optogenética , Receptores de N-Metil-D-Aspartato/metabolismo , Caracteres Sexuales , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Área Tegmental Ventral/efectos de los fármacos , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo
19.
J Neurosci ; 40(17): 3348-3359, 2020 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-32169968

RESUMEN

Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABAA receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca2+ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABAARs synapses through a GΑΒΑ receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca2+-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABAA receptor synapses via Ca2+/calmodulin-dependent protein kinase II. Although Ca2+ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Cerebelo/metabolismo , Interneuronas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Óxido Nítrico/metabolismo , Transducción de Señal/fisiología , Animales , Cerebelo/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Interneuronas/efectos de los fármacos , Masculino , Ratones , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Técnicas de Placa-Clamp , Transducción de Señal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología
20.
Neurotox Res ; 37(3): 702-713, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32062779

RESUMEN

We aimed to investigate whether ethanol (EtOH) and acetaldehyde (AcH) can affect glutamate and its receptors GluN1 and GluA1 in the hippocampus of Aldh2-knockout (Aldh2-KO) and C57BL/6N (wild-type (WT)) mice. To do this, we first examined the effect of local administration of EtOH (100 mM, 200 mM, and 500 mM) and AcH (100 µM, 200 µM, and 500 µM) on extracellular glutamate levels in freely moving mice. Retrodialysis of 200 mM and 500 mM EtOH into the hippocampus of WT and Aldh2-KO mice produced significant decreases in extracellular glutamate levels (p < 0.05). A dose of 500 mM EtOH induced a greater decrease in Aldh2-KO mice (p < 0.05) than in WT mice, indicating the action of AcH. Similarly, perfusion of 200 µM and 500 µM AcH decreased glutamate in Aldh2-KO mice (p < 0.05), but this decrease was not seen in WT mice at any AcH dose. Second, we tested whether the EtOH- and AcH-induced decrease in glutamate was associated with decreases in GluN1 and GluA1 expression, as measured by real-time PCR and Western blot. We found a significant decrease in GluN1 (p < 0.05) and GluA1 (p < 0.05) subunits after a high dose of EtOH (4.0 g/kg) and AcH (200 mg/kg) in WT mice. However, a 2.0 g/kg dose of EtOH did not produce a consistent decrease in GluN1 or GluA1 between messenger RNA and protein. In Aldh2-KO mice, all three doses of EtOH (1.0 g/kg, 2.0 g/kg, and 4.0 g/kg) and AcH (50 mg/kg, 100 mg/kg, and 200 mg/kg) decreased GluN1 expression (p < 0.05), while moderate-to-high doses of EtOH (2.0 g/kg and 4.0 g/kg) and AcH (100 mg/kg and 200 mg/kg) decreased GluA1 expression (p < 0.05). Together, these in vivo and ex vivo data suggest that EtOH and AcH decrease extracellular glutamate in the hippocampus of mice with a concomitant decrease in GluN1 and GluA1 subunits, but these effects require relatively high concentrations and may, therefore, explain the consequences of EtOH intoxication.


Asunto(s)
Acetaldehído/toxicidad , Aldehído Deshidrogenasa Mitocondrial/metabolismo , Etanol/toxicidad , Ácido Glutámico/metabolismo , Hipocampo/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Aldehído Deshidrogenasa Mitocondrial/genética , Animales , Femenino , Hipocampo/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
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