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1.
Brain Behav Immun ; 123: 211-228, 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39293693

RESUMEN

Infection during pregnancy represents a risk factor for neuropsychiatric disorders associated with neurodevelopmental alterations. A growing body of evidence from rodents and non-human primates shows that maternal inflammation induced by viral or bacterial infections results in several neurobiological alterations in the offspring. These changes may play an important role in the pathophysiology of psychiatric disorders like schizophrenia and autism spectrum disorders, whose clinical features include impairments in cognitive processing and social performance. Such alterations are causally associated with the maternal inflammatory response to infection rather than with the infection itself. Previously, we reported that CA1 pyramidal neurons of mice exposed to MIA exhibit increased excitability accompanied by a reduction in dendritic complexity. However, potential alterations in cellular and synaptic rules that shape the neuronal computational properties of the offspring remain to be determined. In this study, using mice as subjects, we identified a series of cellular and synaptic alterations endured by CA1 pyramidal neurons of the dorsal hippocampus in a lipopolysaccharide-induced maternal immune activation (MIA) model. Our data indicate that MIA reshapes the excitation-inhibition balance by decreasing the perisomatic GABAergic inhibition predominantly mediated by cholecystokinin-expressing Interneurons but not parvalbumin-expressing interneurons impinging on CA1 pyramidal neurons. These alterations yield a dysregulated amplification of the temporal and spatial synaptic integration. In addition, MIA-exposed offspring displayed social and anxiety-like abnormalities. These findings collectively contribute to understanding the cellular and synaptic alterations underlying the behavioral symptoms present in neurodevelopmental disorders associated with MIA.

2.
Hippocampus ; 33(8): 906-921, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-36938755

RESUMEN

Experimental manipulations that interfere with the functional expression of N-methyl-D-aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK-801 during early postnatal development alters glutamate release and impairs the induction of NMDAR-dependent long-term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated short- and long-term potentiation, are compromised in response to neonatal treatment with MK-801. Consistent with this tenet, short- and long-term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole-cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre- and postsynaptic modifications at the MF-CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired-pulse ratio, and reduced AMPAR-mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK-801-treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR-independent forms of synaptic plasticity of the hippocampus.


Asunto(s)
Potenciación a Largo Plazo , Receptores de N-Metil-D-Aspartato , Animales , Potenciación a Largo Plazo/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Fibras Musgosas del Hipocampo/fisiología , Maleato de Dizocilpina/farmacología , Células Piramidales/fisiología , Hipocampo/metabolismo , Sinapsis/fisiología , Glutamatos , Transmisión Sináptica/fisiología
3.
Cell Mol Neurobiol ; 43(8): 4007-4022, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37874456

RESUMEN

Growing evidence supports the notion that brain-derived neurotrophic factor (BDNF) and lactate are potent modulators of mammalian brain function. The modulatory actions of those biomolecules influence a wide range of neuronal responses, from the shaping of neuronal excitability to the induction and expression of structural and synaptic plasticity. The biological actions of BDNF and lactate are mediated by their cognate receptors and specific transporters located in the neuronal membrane. Canonical functions of BDNF occur via the tropomyosin-related kinase B receptor (TrkB), whereas lactate acts via monocarboxylate transporters or the hydroxycarboxylic acid receptor 1 (HCAR1). Both receptors are highly expressed in the central nervous system, and some of their physiological actions are particularly well characterized in the hippocampus, a brain structure involved in the neurophysiology of learning and memory. The multifarious neuronal circuitry between the axons of the dentate gyrus granule cells, mossy fibers (MF), and pyramidal neurons of area CA3 is of great interest given its role in specific mnemonic processes and involvement in a growing number of brain disorders. Whereas the modulation exerted by BDNF via TrkB has been extensively studied, the influence of lactate via HCAR1 on the properties of the MF-CA3 circuit is an emerging field. In this review, we discuss the role of both systems in the modulation of brain physiology, with emphasis on the hippocampal CA3 network. We complement this review with original data that suggest cross-modulation is exerted by these two independent neuromodulatory systems.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Fibras Musgosas del Hipocampo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fibras Musgosas del Hipocampo/metabolismo , Ácido Láctico/metabolismo , Hipocampo/metabolismo , Células Piramidales/metabolismo , Proteínas Portadoras/metabolismo , Región CA3 Hipocampal/metabolismo , Mamíferos/metabolismo
4.
Neurochem Res ; 48(7): 2206-2219, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36862323

RESUMEN

Neurogenesis, the formation of new neurons in the brain, occurs throughout the lifespan in the subgranular zone of the dentate gyrus and subventricular zone (SVZ) lining the lateral ventricles of the mammal brain. In this process, gamma-aminobutyric acid (GABA) and its ionotropic receptor, the GABAA receptor (GABAAR), play a critical role in the proliferation, differentiation, and migration process of neural stem/progenitor cells (NPC). Taurine, a non-essential amino acid widely distributed throughout the central nervous system, increases the proliferation of SVZ progenitor cells by a mechanism that may involve GABAAR activation. Therefore, we characterized the effects of taurine on the differentiation process of NPC expressing GABAAR. Preincubation of NPC-SVZ with taurine increased microtubule-stabilizing proteins assessed with the doublecortin assay. Taurine, like GABA, stimulated a neuronal-like morphology of NPC-SVZ and increased the number and length of primary, secondary, and tertiary neurites compared with control NPC of the SVZ. Furthermore, neurite outgrowth was prevented when simultaneously incubating cells with taurine or GABA and the GABAAR blocker, picrotoxin. Patch-clamp recordings revealed a series of modifications in the NPCs' passive and active electrophysiological properties exposed to taurine, including regenerative spikes with kinetic properties similar to the action potentials of functional neurons.


Asunto(s)
Ventrículos Laterales , Células-Madre Neurales , Animales , Taurina/farmacología , Células-Madre Neurales/metabolismo , Diferenciación Celular , Neurogénesis , Ácido gamma-Aminobutírico/metabolismo , Proliferación Celular , Mamíferos
5.
Brain Behav Immun ; 105: 67-81, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35803480

RESUMEN

The epidemiological association between bacterial or viral maternal infections during pregnancy and increased risk for developing psychiatric disorders in offspring is well documented. Numerous rodent and non-human primate studies of viral- or, to a lesser extent, bacterial-induced maternal immune activation (MIA) have documented a series of neurological alterations that may contribute to understanding the pathophysiology of schizophrenia and autism spectrum disorders. Long-term neuronal and behavioral alterations are now ascribed to the effect of maternal proinflammatory cytokines rather than the infection itself. However, detailed electrophysiological alterations in brain areas relevant to psychiatric disorders, such as the dorsal hippocampus, are lacking in response to bacterial-induced MIA. This study determined if electrophysiological and morphological alterations converge in CA1 pyramidal cells (CA1 PC) from the dorsal hippocampus in bacterial-induced MIA offspring. A series of changes in the functional expression of K+ and Na+ ion channels altered the passive and active membrane properties and triggered hyperexcitability of CA1 PC. Contributing to the hyperexcitability, the somatic A-type potassium current (IA) was decreased in MIA CA1 PC. Likewise, the spontaneous glutamatergic and GABAergic inputs were dysregulated and biased toward increased excitation, thereby reshaping the excitation-inhibition balance. Consistent with these findings, the dendritic branching complexity of MIA CA1 PC was reduced. Together, these morphophysiological alterations modify CA1 PC computational capabilities and contribute to explaining cellular alterations that may underlie the cognitive symptoms of MIA-associated psychiatric disorders.


Asunto(s)
Inmunidad , Neuronas , Canales de Potasio , Animales , Trastorno del Espectro Autista/inmunología , Región CA1 Hipocampal/citología , Regulación hacia Abajo , Femenino , Neuronas/metabolismo , Canales de Potasio/metabolismo , Embarazo , Células Piramidales/inmunología , Esquizofrenia/inmunología
6.
Sensors (Basel) ; 22(3)2022 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-35162025

RESUMEN

Video tracking involves detecting previously designated objects of interest within a sequence of image frames. It can be applied in robotics, unmanned vehicles, and automation, among other fields of interest. Video tracking is still regarded as an open problem due to a number of obstacles that still need to be overcome, including the need for high precision and real-time results, as well as portability and low-power demands. This work presents the design, implementation and assessment of a low-power embedded system based on an SoC-FPGA platform and the honeybee search algorithm (HSA) for real-time video tracking. HSA is a meta-heuristic that combines evolutionary computing and swarm intelligence techniques. Our findings demonstrated that the combination of SoC-FPGA and HSA reduced the consumption of computational resources, allowing real-time multiprocessing without a reduction in precision, and with the advantage of lower power consumption, which enabled portability. A starker difference was observed when measuring the power consumption. The proposed SoC-FPGA system consumed about 5 Watts, whereas the CPU-GPU system required more than 200 Watts. A general recommendation obtained from this research is to use SoC-FPGA over CPU-GPU to work with meta-heuristics in computer vision applications when an embedded solution is required.


Asunto(s)
Algoritmos , Programas Informáticos , Animales , Abejas
7.
Toxicol Appl Pharmacol ; 395: 114980, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32234516

RESUMEN

Toluene can be intentionally misused by adolescents to experience psychoactive effects. Toluene has a complex mechanism of action and broad behavioral effects, among which memory impairment is reported consistently. We have previously reported that repeated toluene inhalation (8000 ppm) increases layer 5 prelimbic pyramidal cells' excitability in the medial prefrontal cortex (mPFC) of adolescent rats. Toluene also produces reactive oxygen species (ROS), which activate glial cells. Here, we tested the hypothesis that the anti-inflammatory agent minocycline would decrease toluene's effects because it inhibits NF-κB (nuclear factor enhancer of the kappa light chains of activated B cells) and reduces pro-inflammatory cytokine and ROS production. Our results show that minocycline (50 mg/kg, ip, for 10 days) prevents the hyperexcitability of mPFC neurons observed after repeated 8000 ppm toluene exposure (30 min/day, 2×/day for 10 days). Minocycline prevents toluene-induced hyperexcitability by a mechanism that averts the loss of the slow calcium-dependent potassium current, and normalizes mPFC neurons' firing frequency. These effects are accompanied by significant decreased expression of astrocytes and activated microglia in the mPFC, reduced NLRP3 inflammasome activation and mRNA expression levels of the pro-inflammatory cytokine interleukin 1ß (IL-1ß), as well as increased mRNA expression of the anti-inflammatory cytokine transforming growth factor ß (TGF-ß). Minocycline also prevents toluene-induced memory impairment in adolescent rats in the passive avoidance task and the temporal order memory test in which the mPFC plays a central role. These results show that neuroinflammation produces several effects of repeated toluene administration at high concentrations, and minocycline can significantly prevent them.


Asunto(s)
Antiinflamatorios/administración & dosificación , Trastornos de la Memoria/prevención & control , Minociclina/administración & dosificación , Neuronas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Tolueno/toxicidad , Administración por Inhalación , Animales , Expresión Génica/efectos de los fármacos , Abuso de Inhalantes , Interleucina-1beta/genética , Masculino , Trastornos de la Memoria/inducido químicamente , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Neuronas/fisiología , Corteza Prefrontal/patología , Corteza Prefrontal/fisiopatología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Tolueno/administración & dosificación , Factor de Crecimiento Transformador beta/genética
8.
Purinergic Signal ; 15(1): 85-93, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30565027

RESUMEN

We previously reported that the activation of histamine H3 receptors (H3Rs) selectively counteracts the facilitatory action of adenosine A2A receptors (A2ARs) on GABA release from rat globus pallidus (GP) isolated nerve terminals (synaptosomes). In this work, we examined the mechanisms likely to underlie this functional interaction. Three possibilities were explored: (a) changes in receptor affinity for agonists induced by physical A2AR/H3R interaction, (b) opposite actions of A2ARs and H3Rs on depolarization-induced Ca2+ entry, and (c) an A2AR/H3R interaction at the level of adenosine 3',5'-cyclic monophosphate (cAMP) formation. In GP synaptosomal membranes, H3R activation with immepip reduced A2AR affinity for the agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680) (Ki control 4.53 nM; + immepip 9.32 nM), whereas A2AR activation increased H3R affinity for immepip (Ki control 0.63 nM; + CGS-21680 0.26 nM). Neither A2AR activation nor H3R stimulation modified calcium entry through voltage-gated calcium channels in GP synaptosomes, as evaluated by microfluorometry. A2AR-mediated facilitation of depolarization-evoked [2,3-3H]-γ-aminobutyric acid ([3H]-GABA) release from GP synaptosomes (130.4 ± 3.6% of control values) was prevented by the PKA inhibitor H-89 and mimicked by the adenylyl cyclase activator forskolin or by 8-Bromo-cAMP, a membrane permeant cAMP analogue (169.5 ± 17.3 and 149.5 ± 14.5% of controls). H3R activation failed to reduce the facilitation of [3H]-GABA release induced by 8-Bromo-cAMP. In GP slices, A2AR activation stimulated cAMP accumulation (290% of basal) and this effect was reduced (- 75%) by H3R activation. These results indicate that in striato-pallidal nerve terminals, A2ARs and H3Rs interact at the level of cAMP formation to modulate PKA activity and thus GABA release.


Asunto(s)
Globo Pálido/metabolismo , Receptor de Adenosina A2A/metabolismo , Receptores Histamínicos H3/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Potenciales Evocados/fisiología , Masculino , Ratas , Ratas Wistar
9.
J Neurosci ; 37(3): 701-714, 2017 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-28100750

RESUMEN

The mossy fibers (MFs) corelease glutamate and GABA onto pyramidal cells of CA3 during development, until the end of the third postnatal week. However, the major target cells of the MF are the interneurons of CA3. Therefore, it has been shown that the interneurons of the hilus and stratum lucidum receive this dual monosynaptic input on MF stimulation. Because the plasticity of glutamatergic transmission from the different terminals of the MF is target specific, we here asked whether the corelease of glutamate and GABA was also subjected to a target-dependent compartmentalization. We analyzed the occurrence and plasticity of MF simultaneous glutamatergic-GABAergic signaling onto interneurons of the different strata of CA3 in rats during the third postnatal week. We show the coexistence of time-locked, glutamate receptor and GABA receptor-mediated mono synaptic responses evoked by MF stimulation in interneurons from stratum lucidum and stratum radiatum, but not in interneurons from stratum lacunosum-moleculare. As expected from the transmission of MF origin, MF GABAergic responses were depressed by the activation of metabotropic glutamate receptors. Strikingly, while MF glutamatergic responses underwent LTD, the simultaneous MF GABAergic responses of stratum lucidum interneurons, but not of stratum radiatum interneurons, displayed a Hebbian form of LTP that was mimicked by PKC activation. PKA activation potentiated MF glutamatergic responses of stratum radiatum interneurons, whereas in stratum lucidum interneurons only GABAergic responses were potentiated. We here disclose that the corelease of glutamate and GABA, as well as their plasticity are compartmentalized in a target-dependent manner, showing counterbalanced compensatory plasticity of two neurotransmitters released by different terminals of the same pathway. SIGNIFICANCE STATEMENT: The mossy fibers transiently corelease glutamate and GABA onto pyramidal cells of CA3. We here describe that they can also corelease these amino acids onto interneurons, in a target-dependent manner. Many interneurons in stratum lucidum and stratum radiatum receive both signals, while those in stratum lacunosum-moleculare exclusively receive a glutamatergic signal. It is noteworthy that glutamatergic LTD, which is known to exist on stratum lucidum interneurons, coexists in the same pathway with a presynaptic form of GABAergic LTP, while interneurons of stratum radiatum, despite receiving this dual signaling, do not display such plasticity. The GABAergic LTP is mimicked with PKA or PKC activation. We disclose compartmentalized corelease of glutamate and GABA and its differential plasticity from a single pathway onto different interneuron sets.


Asunto(s)
Ácido Glutámico/metabolismo , Interneuronas/metabolismo , Fibras Musgosas del Hipocampo/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Potenciales de Acción/fisiología , Animales , Masculino , Técnicas de Cultivo de Órganos , Ratas , Ratas Wistar
10.
Hippocampus ; 28(8): 557-567, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29704292

RESUMEN

In addition to its prominent role as an energetic substrate in the brain, lactate is emerging as a signaling molecule capable of controlling neuronal excitability. The finding that the lactate-activated receptor (hydroxycarboxylic acid receptor 1; HCA1) is widely expressed in the brain opened up the possibility that lactate exerts modulation of neuronal activity via a transmembranal receptor-linked mechanism. Here, we show that lactate causes biphasic modulation of the intrinsic excitability of CA1 pyramidal cells. In the low millimolar range, lactate or the HCA1 agonist 3,5-DHBA reduced the input resistance and membrane time constant. In addition, activation of HCA1 significantly blocked the fast inactivating sodium current and increased the delay from inactivation to a conducting state of the sodium channel. As the observed actions occurred in the presence of 4-CIN, a blocker of the neuronal monocarboxylate transporter, the possibility that lactate acted via neuronal metabolism is unlikely. Consistently, modulation of the intrinsic excitability was abolished when CA1 pyramidal cells were dialyzed with pertussis toxin, indicating the dependency of a Gαi/o -protein-coupled receptor. The activation of HCA1 appears to serve as a restraining mechanism during enhanced network activity and may function as a negative feedback for the astrocytic production of lactate.


Asunto(s)
Hipocampo/fisiología , Receptores Acoplados a Proteínas G/metabolismo , 4-Aminopiridina/farmacología , Animales , Biofisica , Cinamatos/farmacología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hidroxibenzoatos/farmacología , Técnicas In Vitro , Ácido Láctico/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Células Piramidales/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Resorcinoles/farmacología
11.
Eur J Neurosci ; 47(9): 1096-1109, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29480936

RESUMEN

The selective vulnerability of hippocampal area CA1 to ischemia-induced injury is a well-known phenomenon. However, the cellular mechanisms that confer resistance to area CA3 against ischemic damage remain elusive. Here, we show that oxygen-glucose deprivation-reperfusion (OGD-RP), an in vitro model that mimic the pathological conditions of the ischemic stroke, increases the phosphorylation level of tropomyosin receptor kinase B (TrkB) in area CA3. Slices preincubated with brain-derived neurotrophic factor (BDNF) or 7,8-dihydroxyflavone (7,8-DHF) exhibited reduced depression of the electrical activity triggered by OGD-RP. Consistently, blockade of TrkB suppressed the resistance of area CA3 to OGD-RP. The protective effect of TrkB activation was limited to area CA3, as OGD-RP caused permanent suppression of CA1 responses. At the cellular level, TrkB activation leads to phosphorylation of the accessory proteins SHC and Gab as well as the serine/threonine kinase Akt, members of the phosphoinositide 3-kinase/Akt (PI-3-K/Akt) pathway, a cascade involved in cell survival. Hence, acute slices pretreated with the Akt antagonist MK2206 in combination with BDNF lost the capability to resist the damage inflicted with OGD-RP. Consistently, with these results, CA3 pyramidal cells exhibited reduced propidium iodide uptake and caspase-3 activity in slices pretreated with BDNF and exposed to OGD-RP. We propose that PI-3-K/Akt downstream activation mediated by TrkB represents an endogenous mechanism responsible for the resistance of area CA3 to ischemic damage.


Asunto(s)
Glucosa/metabolismo , Hipocampo/metabolismo , Oxígeno/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor trkB/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Hipocampo/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos
12.
Br J Pharmacol ; 181(16): 2701-2724, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38631821

RESUMEN

BACKGROUND AND PURPOSE: Transient hypofunction of the NMDA receptor represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant pathway synapses, have barely been explored in this pathological condition. EXPERIMENTAL APPROACH: We identified a series of synaptic alterations of the lateral and medial perforant paths in animals postnatally treated with the NMDA antagonist MK-801. This dysregulation suggests decreased cognitive performance, for which the dentate gyrus is critical. KEY RESULTS: We identified alterations in the synaptic properties of the lateral and medial perforant paths to the dentate gyrus synapses in slices from MK-801-treated animals. Altered glutamate release and decreased synaptic strength precede an impairment in the induction and expression of long-term potentiation (LTP) and CB1 receptor-mediated long-term depression (LTD). Remarkably, by inhibiting the degradation of 2-arachidonoylglycerol (2-AG), an endogenous ligand of the CB1 receptor, we restored the LTD in animals treated with MK-801. Additionally, we showed for the first time, that spatial discrimination, a cognitive task that requires dentate gyrus integrity, is impaired in animals exposed to transient hypofunction of NMDA receptors. CONCLUSION AND IMPLICATIONS: Dysregulation of glutamatergic transmission and synaptic plasticity from the entorhinal cortex to the dentate gyrus has been demonstrated, which may explain the cellular dysregulations underlying the altered cognitive processing in the dentate gyrus associated with schizophrenia.


Asunto(s)
Giro Dentado , Maleato de Dizocilpina , Plasticidad Neuronal , Vía Perforante , Receptores de N-Metil-D-Aspartato , Animales , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Maleato de Dizocilpina/farmacología , Vía Perforante/efectos de los fármacos , Vía Perforante/fisiología , Plasticidad Neuronal/efectos de los fármacos , Masculino , Ratas , Endocannabinoides/metabolismo , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB1/antagonistas & inhibidores , Ratas Wistar , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciación a Largo Plazo/efectos de los fármacos
13.
PLoS One ; 19(6): e0305853, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38913632

RESUMEN

The intricate process of neuronal differentiation integrates multiple signals to induce transcriptional, morphological, and electrophysiological changes that reshape the properties of neural precursor cells during their maturation and migration process. An increasing number of neurotransmitters and biomolecules have been identified as molecular signals that trigger and guide this process. In this sense, taurine, a sulfur-containing, non-essential amino acid widely expressed in the mammal brain, modulates the neuronal differentiation process. In this study, we describe the effect of taurine acting via the ionotropic GABAA receptor and the metabotropic GABAB receptor on the neuronal differentiation and electrophysiological properties of precursor cells derived from the subventricular zone of the mouse brain. Taurine stimulates the number of neurites and favors the dendritic complexity of the neural precursor cells, accompanied by changes in the somatic input resistance and the strength of inward and outward membranal currents. At the pharmacological level, the blockade of GABAA receptors inhibits these effects, whereas the stimulation of GABAB receptors has no positive effects on the taurine-mediated differentiation process. Strikingly, the blockade of the GABAB receptor with CGP533737 stimulates neurite outgrowth, dendritic complexity, and membranal current kinetics of neural precursor cells. The effects of taurine on the differentiation process involve Ca2+ mobilization and the activation of intracellular signaling cascades since chelation of intracellular calcium with BAPTA-AM, and inhibition of the CaMKII, ERK1/2, and Src kinase inhibits the neurite outgrowth of neural precursor cells of the subventricular zone.


Asunto(s)
Diferenciación Celular , Ventrículos Laterales , Células-Madre Neurales , Receptores de GABA-A , Receptores de GABA-B , Animales , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Receptores de GABA-B/metabolismo , Ratones , Diferenciación Celular/efectos de los fármacos , Receptores de GABA-A/metabolismo , Ventrículos Laterales/citología , Ventrículos Laterales/metabolismo , Taurina/farmacología , Neurogénesis/efectos de los fármacos , Calcio/metabolismo
14.
Hippocampus ; 23(4): 247-52, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23436451

RESUMEN

Synaptic transmission of the granule cells (GCs) via their axons, the mossy fibers (MFs), is traditionally studied on acutely prepared or cultured slices. Usually, extracellular, bulk or minimal stimulation is used to evoke transmitter release from MF terminals, while recording from their postsynaptic target cells, the pyramidal cells and interneurons of CA3. However, the ideal method to assess MF neurotransmission, the simultaneous recording of a presynaptic GC and one of its target cells, is extremely difficult to achieve using slices. Alternatively, cultures of GCs establishing autapses have been developed, but in these, GCs do not contact their natural targets. We developed cocultures of GCs, dissociated from transgenic GFP(+) rats, with pyramidal cells and interneurons of CA3, dissociated from wild-type rats, and confirmed the expression of cell-specific markers by immunofluorescence. We conducted recordings of GFP(+) -GCs synaptically connected with their GFP(-) -target cells, and demonstrate that synaptic transmission and its plasticity have the signature of transmission of MF. Besides being strongly depressed by activation of mGluRs, high frequency activation of GC-to-pyramidal cells synapses undergo LTP, while GC-to-interneuron synapses undergo LTD. This coculture method allows a high reproducibility of recording connected pairs of identified cells, constituting a valuable tool to study MF transmission, as well as different combinations of identifiable pre- and postsynaptic cells.


Asunto(s)
Potenciales Postsinápticos Excitadores/fisiología , Proteínas Fluorescentes Verdes/metabolismo , Interneuronas/fisiología , Fibras Musgosas del Hipocampo/fisiología , Células Piramidales/fisiología , Transmisión Sináptica/fisiología , Animales , Células Cultivadas , Técnicas de Cocultivo , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Proteínas Fluorescentes Verdes/genética , Hipocampo/citología , Potenciación a Largo Plazo/efectos de los fármacos , Fibras Musgosas del Hipocampo/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacos
15.
Neuroscience ; 532: 65-78, 2023 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-37776946

RESUMEN

The blockade of 5-HT6 receptors represents an experimental approach that might ameliorate the memory deficits associated with brain disorders, including Alzheimer's disease and schizophrenia. However, the synaptic mechanism by which 5-HT6 receptors control the GABAergic and glutamatergic synaptic transmission is barely understood. In this study, we demonstrate that pharmacological manipulation of 5-HT6 receptors with the specific agonist EMD 386088 (7.4 nM) or the antagonist SB-399885 (300 nM) modulates the field inhibitory postsynaptic potentials of the dorsal hippocampus and controls the strength of the population spike of pyramidal cells. Likewise, pharmacological modulation of 5-HT6 controls the magnitude of paired-pulse inhibition, a phenomenon mediated by GABAergic interneurons acting via GABAA receptors of pyramidal cells. The effects of pharmacological manipulation of the 5-HT6 receptor were limited to GABAergic transmission and did not affect the strength of field excitatory postsynaptic potentials mediated by the Schaffer collaterals axons. Lastly, in a modified version of the Pavlovian autoshaping task that requires the activation of the hippocampal formation, we demonstrated that the anti-amnesic effect induced by the blockade of the 5-HT6 receptor is prevented when the GAT1 transporter is blocked, suggesting that modulation of GABAergic transmission is required for the anti-amnesic properties of 5-HT6 receptor antagonists.


Asunto(s)
Hipocampo , Receptores de Serotonina , Ratas , Animales , Ratas Wistar , Receptores de Serotonina/metabolismo , Células Piramidales/fisiología , Transmisión Sináptica/fisiología , Receptores de GABA-A
16.
Cell Transplant ; 32: 9636897231177357, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37291807

RESUMEN

Obesity has been linked to cognitive impairment through systemic low-grade inflammation. High fat and sugar diets (HFSDs) also induce systemic inflammation, either by induced Toll-like receptor 4 response, or by causing dysbiosis. This study aimed to evaluate the effect of symbiotics supplementation on spatial and working memory, butyrate concentration, neurogenesis, and electrophysiological recovery of HFSD-fed rats. In a first experiment, Sprague-Dawley male rats were given HFSD for 10 weeks, after which they were randomized into 2 groups (n = 10 per group): water (control), or Enterococcus faecium + inulin (symbiotic) administration, for 5 weeks. In the fifth week, spatial and working memory was analyzed through the Morris Water Maze (MWM) and Eight-Arm Radial Maze (RAM) tests, respectively, with 1 week apart between tests. At the end of the study, butyrate levels from feces and neurogenesis at hippocampus were determined. In a second experiment with similar characteristics, the hippocampus was extracted to perform electrophysiological studies. Symbiotic-supplemented rats showed a significantly better memory, butyrate concentrations, and neurogenesis. This group also presented an increased firing frequency in hippocampal neurons [and a larger N-methyl-d-aspartate (NMDA)/α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) current ratio] suggesting an increase in NMDA receptors, which in turn is associated with an enhancement in long-term potentiation and synaptic plasticity. Therefore, our results suggest that symbiotics could restore obesity-related memory impairment and promote synaptic plasticity.


Asunto(s)
Agave , Memoria Espacial , Ratas , Animales , Masculino , Agave/metabolismo , Inulina/farmacología , Inulina/uso terapéutico , Ratas Sprague-Dawley , Hipocampo/metabolismo , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Aprendizaje por Laberinto/fisiología , Obesidad/terapia , Suplementos Dietéticos , Inflamación
17.
Biomedicines ; 11(12)2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-38137458

RESUMEN

Drug-resistant epilepsy (DRE) is associated with high extracellular levels of glutamate. Studies support the idea that cannabidiol (CBD) decreases glutamate over-release. This study focused on investigating whether CBD reduces the evoked glutamate release in cortical synaptic terminals obtained from patients with DRE as well as in a preclinical model of epilepsy. Synaptic terminals (synaptosomes) were obtained from the epileptic neocortex of patients with drug-resistant temporal lobe epilepsy (DR-TLE, n = 10) or drug-resistant extratemporal lobe epilepsy (DR-ETLE, n = 10) submitted to epilepsy surgery. Synaptosomes highly purified by Percoll-sucrose density gradient were characterized by confocal microscopy and Western blot. Synaptosomes were used to estimate the high KCl (33 mM)-evoked glutamate release in the presence of CBD at different concentrations. Our results revealed responsive tissue obtained from seven patients with DR-TLE and seven patients with DR-ETLE. Responsive tissue showed lower glutamate release (p < 0.05) when incubated with CBD at low concentrations (less than 100 µM) but not at higher concentrations. Tissue that was non-responsive to CBD (DR-TLE, n = 3 and DR-ELTE, n = 3) showed high glutamate release despite CBD exposure at different concentrations. Simultaneously, a block of the human epileptic neocortex was used to determine its viability through whole-cell and extracellular electrophysiological recordings. The electrophysiological evaluations supported that the responsive and non-responsive human epileptic neocortices used in the present study exhibited proper neuronal viability and stability to acquire electrophysiological responses. We also investigated whether the subchronic administration of CBD could reduce glutamate over-release in a preclinical model of temporal lobe epilepsy. Administration of CBD (200 mg/kg, p.o. every 24 h for 7 days) to rats with lithium-pilocarpine-evoked spontaneous recurrent seizures reduced glutamate over-release in the hippocampus. The present study revealed that acute exposure to low concentrations of CBD can reduce the glutamate over-release in synaptic terminals obtained from some patients with DRE. This effect is also evident when applied subchronically in rats with spontaneous recurrent seizures. An important finding was the identification of a group of patients that were non-responsive to CBD effects. Future studies are essential to identify biomarkers of responsiveness to CBD to control DRE.

18.
Neurobiol Aging ; 112: 27-38, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35041997

RESUMEN

Neuronal processing from the dentate gyrus to the hippocampus is critical for storage and recovery of new memory traces. In area CA3, GABAergic interneurons form a strong barrage of inhibition that modulates pyramidal cells. A well-established feature of aging is decreased GABAergic inhibition, a phenomenon that contributes to the exacerbated excitability of aged pyramidal cells. In hippocampal slices of aged rats (22-28 months old) we examined the properties of regular spiking CA3 interneurons with patch-clamp whole-cell recordings. We found enhanced firing discharge without altering the maximal firing rate of aged regular spiking interneurons. In the mossy fibers (MF) to interneurons synapse, a switch in the AMPA receptor subunit composition was found in aged interneurons. Young regular spiking interneurons predominantly express CP AMPA receptors and MF LTD. By contrast, aged regular spiking interneurons contain a higher proportion of CI AMPA receptors and respond with MF LTP. We show for the first time that the specialized MF terminals contacting interneurons, retain synaptic capabilities and provide a novel insight of the interneuron's function during aging.


Asunto(s)
Interneuronas , Fibras Musgosas del Hipocampo , Animales , Hipocampo , Interneuronas/fisiología , Células Piramidales/fisiología , Ratas , Sinapsis/fisiología , Transmisión Sináptica/fisiología
19.
Neurotoxicology ; 91: 128-139, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35580742

RESUMEN

In C57BL/6 J mice, systemic inflammation was induced by administering bacterial LPS (1 mg/kg) intraperitoneally. In response, animals exhibited hypokinesia, piloerection, and a slight decrease in body temperature accompanied by increased serum levels of the proinflammatory cytokine TNF-α. 24 h after the immunogenic challenge, acute cortical slices were prepared, and whole-cell patch-clamp recordings were performed in morphologically identified prelimbic neurons of the mice's prefrontal cortex. Electrophysiologic alterations included changes in the kinetics parameters of the fast-inactivating sodium and slow-inactivating potassium currents. In current-clamp mode, our recordings revealed alterations in several conductances that shape the intrinsic excitability of prelimbic neurons. The action potential exhibited changes in latency, amplitude, and the rheobase current to elicit firing discharge. Likewise, phase plots of the action potentials uncovered alterations in the repetitive firing of prelimbic neurons. Consistent with these changes, the afterhyperpolarization conductance and the slowly decaying, calcium-dependent after-hyperpolarization current that follows an action potential were decreased in response to systemic LPS. Our data demonstrate that immune activation alters the ionic currents that shape the intrinsic excitability and predicts dysregulation of non-synaptic forms of neuronal plasticity modulated by the intrinsic excitability of prefrontal cortex neurons.


Asunto(s)
Potasio , Sodio , Potenciales de Acción/fisiología , Animales , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Neuronas/fisiología , Potasio/fisiología
20.
Br J Pharmacol ; 179(8): 1695-1715, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34791647

RESUMEN

BACKGROUND AND PURPOSE: Dysregulation of dopaminergic transmission combined with transient hypofunction of N-methyl-d-aspartate receptors (NMDARs) is a key mechanism that may underlie cognitive symptoms of schizophrenia. EXPERIMENTAL APPROACH: Therefore, we aimed to identify electrophysiologic alterations in animals neonatally treated with the NMDA receptor antagonist, MK-801, or with saline solution. KEY RESULTS: Patch-clamp whole-cell recordings from MK-801-treated animals revealed altered passive and active electrophysiologic properties compared with CA1 pyramidal cells from saline-treated animals, including up-regulation of the K+ inward-rectifier conductance and fast-inactivating and slow/non-inactivating K+ currents. Up-regulation of these membrane ionic currents reduced the overall excitability and altered the firing properties of CA1 pyramidal cells. We also explored the capability of cells treated with MK-801 to express intrinsic excitability potentiation, a non-synaptic form of hippocampal plasticity associated with cognition and memory formation. CA1 pyramidal cells from animals treated with MK-801 were unable to convey intrinsic excitability potentiation and had blunted synaptic potentiation. Furthermore, MK-801-treated animals also exhibited reduced cognitive performance in the Barnes maze task. Notably, activation of D1/D5 receptors with SKF-38,393 partially restored electrophysiologic alterations caused by neonatal treatment with MK-801. CONCLUSION AND IMPLICATIONS: Our results offer a molecular and mechanistic explanation based on dysregulation of glutamatergic transmission, in addition to dopaminergic transmission, that may contribute to the understanding of the cognitive deterioration associated with schizophrenia.


Asunto(s)
Maleato de Dizocilpina , Receptores de Dopamina D1 , Receptores de Dopamina D5 , Receptores de N-Metil-D-Aspartato , Animales , Maleato de Dizocilpina/farmacología , Dopamina/farmacología , Hipocampo/metabolismo , Neuronas/metabolismo , Células Piramidales/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica
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