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Human evolution is characterized by rapid brain enlargement and the emergence of unique cognitive abilities. Besides its distinctive cytoarchitectural organization and extensive inter-neuronal connectivity, the human brain is also defined by high rates of synaptic, mainly glutamatergic, transmission, and energy utilization. While these adaptations' origins remain elusive, evolutionary changes occurred in synaptic glutamate metabolism in the common ancestor of humans and apes via the emergence of GLUD2, a gene encoding the human glutamate dehydrogenase 2 (hGDH2) isoenzyme. Driven by positive selection, hGDH2 became adapted to function upon intense excitatory firing, a process central to the long-term strengthening of synaptic connections. It also gained expression in brain astrocytes and cortical pyramidal neurons, including the CA1-CA3 hippocampal cells, neurons crucial to cognition. In mice transgenic for GLUD2, theta-burst-evoked long-term potentiation (LTP) is markedly enhanced in hippocampal CA3-CA1 synapses, with patch-clamp recordings from CA1 pyramidal neurons revealing increased sNMDA receptor currents. D-lactate blocked LTP enhancement, implying that glutamate metabolism via hGDH2 potentiates L-lactate-dependent glia-neuron interaction, a process essential to memory consolidation. The transgenic (Tg) mice exhibited increased dendritic spine density/synaptogenesis in the hippocampus and improved complex cognitive functions. Hence, enhancement of neuron-glia communication, via GLUD2 evolution, likely contributed to human cognitive advancement by potentiating synaptic plasticity and inter-neuronal connectivity.
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Cognición , Glutamato Deshidrogenasa , Ácido Glutámico , Plasticidad Neuronal , Animales , Humanos , Ácido Glutámico/metabolismo , Cognición/fisiología , Glutamato Deshidrogenasa/metabolismo , Glutamato Deshidrogenasa/genética , Ratones , Ácido Láctico/metabolismo , Potenciación a Largo Plazo , Ratones Transgénicos , Células Piramidales/metabolismo , Hipocampo/metabolismo , Evolución Molecular , Sinapsis/metabolismoRESUMEN
The human brain is characterized by the upregulation of synaptic, mainly glutamatergic, transmission, but its evolutionary origin(s) remain elusive. Here we approached this fundamental question by studying mice transgenic (Tg) for GLUD2, a human gene involved in glutamate metabolism that emerged in the hominoid and evolved concomitantly with brain expansion. We demonstrate that Tg mice express the human enzyme in hippocampal astrocytes and CA1-CA3 pyramidal neurons. LTP, evoked by theta-burst stimulation, is markedly enhanced in the CA3-CA1 synapses of Tg mice, with patch-clamp recordings from CA1 pyramidal neurons revealing increased sNMDA currents. LTP enhancement is blocked by D-lactate, implying that GLUD2 potentiates L-lactate-mediated astrocyte-neuron interaction. Dendritic spine density and synaptogenesis are increased in the hippocampus of Tg mice, which exhibit enhanced responses to sensory stimuli and improved performance on complex memory tasks. Hence, GLUD2 likely contributed to human brain evolution by enhancing synaptic plasticity and metabolic processes central to cognitive functions.
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Local anesthetics occupy a prime position in clinical medicine as they temporarily relieve the pain by blocking voltage-gated sodium channels. However, limited structural diversity, problems with the efficiency of syntheses and increasing toxicity, mean that alternative scaffolds with improved chemical syntheses are urgently needed. Here, we demonstrate a multicomponent reaction (MCR)-based approach both towards the synthesis of commercial local anesthetics and towards novel derivatives as potential anesthesia candidates via scaffold hopping. The reactions are efficient and scalable, and several single-crystal structures have been obtained. In addition, our methodology has been applied to the synthesis of the antianginal drug ranolazine, via an Ugi three-component reaction. Representative derivatives from our libraries were evaluated as neuronal activity inhibitors using local field potential recordings (LFPs) in mouse hippocampal brain slices and showed very promising results. This study highlights new opportunities in drug discovery targeting local anesthetics.
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Anestésicos Locales , Descubrimiento de Drogas , Anestésicos Locales/farmacología , Animales , RatonesRESUMEN
Neurotrophins are growth factors that exert important neuroprotective effects by preventing neuronal death and synaptic loss. Nerve Growth Factor (NGF) acts through the activation of its high-affinity, pro-survival TrkA and low-affinity, pro-apoptotic p75NTR receptors. NGF has been shown to slow or prevent neurodegenerative signals in Alzheimer's Disease (AD) progression. However, its low bioavailability and its blood-brain-barrier impermeability limit the use of NGF as a potential therapeutic agent against AD. Based on our previous findings on synthetic dehydroepiandrosterone derivatives, we identified a novel NGF mimetic, named ENT-A013, which selectively activates TrkA and exerts neuroprotective, anti-amyloid-ß actions. We now report the chemical synthesis, in silico modelling, metabolic stability, CYP-mediated reaction phenotyping and biological characterization of ENT-A013 under physiological and neurodegenerative conditions. We show that ENT-A013 selectively activates the TrkA receptor and its downstream kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death. Moreover, ENT-A013 promotes survival of primary Dorsal Root Ganglion (DRG) neurons upon NGF withdrawal and protects hippocampal neurons against Amyloid ß-induced apoptosis and synaptic loss. Furthermore, this neurotrophin mimetic partially restores LTP impairment. In conclusion, ENT-A013 represents a promising new lead molecule for developing therapeutics against neurodegenerative disorders, such as Alzheimer's Disease, selectively targeting TrkA-mediated pro-survival signals.
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The pruning of dendritic spines during development requires autophagy. This process is facilitated by long-term depression (LTD)-like mechanisms, which has led to speculation that LTD, a fundamental form of synaptic plasticity, also requires autophagy. Here, we show that the induction of LTD via activation of NMDA receptors or metabotropic glutamate receptors initiates autophagy in the postsynaptic dendrites in mice. Dendritic autophagic vesicles (AVs) act in parallel with the endocytic machinery to remove AMPA receptor subunits from the membrane for degradation. During NMDAR-LTD, key postsynaptic proteins are sequestered for autophagic degradation, as revealed by quantitative proteomic profiling of purified AVs. Pharmacological inhibition of AV biogenesis, or conditional ablation of atg5 in pyramidal neurons abolishes LTD and triggers sustained potentiation in the hippocampus. These deficits in synaptic plasticity are recapitulated by knockdown of atg5 specifically in postsynaptic pyramidal neurons in the CA1 area. Conducive to the role of synaptic plasticity in behavioral flexibility, mice with autophagy deficiency in excitatory neurons exhibit altered response in reversal learning. Therefore, local assembly of the autophagic machinery in dendrites ensures the degradation of postsynaptic components and facilitates LTD expression.
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Autofagia/fisiología , Espinas Dendríticas/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Proteoma/metabolismo , Proteómica/métodos , Potenciales Sinápticos/fisiología , Animales , Autofagia/genética , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Células Cultivadas , Hipocampo/citología , Hipocampo/metabolismo , Hipocampo/fisiología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Células Piramidales/metabolismo , Células Piramidales/fisiología , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The prefrontal cortex (PFC) is characterized by protracted maturation. The cellular mechanisms controlling the early development of prefrontal circuits are still largely unknown. Our study delineates the developmental cellular processes in the mouse medial PFC (mPFC) during the second and the third postnatal weeks and characterizes their contribution to the changes in network activity. We show that spontaneous inhibitory postsynaptic currents (sIPSC) are increased, whereas spontaneous excitatory postsynaptic currents (sEPSC) are reduced from the second to the third postnatal week. Drug application suggested that the increased sEPSC frequency in mPFC at postnatal day 10 (P10) is due to depolarizing γ-aminobutyric acid (GABA) type A receptor function. To further validate this, perforated patch-clamp recordings were obtained and the expression levels of K-Cl cotransporter 2 (KCC2) protein were examined. The reversal potential of IPSCs in response to current stimulation was significantly more depolarized at P10 than P20 while KCC2 expression is decreased. Moreover, the number of parvalbumin-expressing GABAergic interneurons increases and their intrinsic electrophysiological properties significantly mature in the mPFC from P10 to P20. Using computational modeling, we show that the developmental changes in synaptic and intrinsic properties of mPFC neurons contribute to the enhanced network activity in the juvenile compared with neonatal mPFC.
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Simportadores , Ácido gamma-Aminobutírico , Animales , Potenciales Postsinápticos Excitadores/fisiología , Ratones , Neuronas/fisiología , Técnicas de Placa-Clamp , Simportadores/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Stress, a major regulator and precipitating factor of cognitive and emotional disorders, differentially manifests between males and females. Our aim was to investigate the mechanisms underlying the sexual dimorphic effects of acute restraint stress (RS) on males and females on the function of the prefrontal cortex (PFC). Adult male and female mice were subjected to RS or left in their home-cage (NR), and then tested in the light-dark test followed by the temporal order object recognition (TOR) task. Female mice exhibited increased anxiety-like levels, whereas male mice only showed deficits in the TOR task. When the behavioural tests were conducted 24 hr following restraint stress (RS24), only the reduced performance in the TOR task in male mice persisted. In a different cohort, evoked field excitatory postsynaptic potentials (fEPSPs) were recorded in layer II of acute PFC slices, immediately or 24 hr after RS. Long-term potentiation (LTP) was significantly reduced in RS and RS24 male, but not female, compared with their respective NR group. LTP in PFC slices incubated with corticosterone showed significantly reduced LTP only in males. To determine whether glucocorticoid signalling is implicated in the RS-induced behavioural effects, a different cohort of mice was administered mifepristone, a corticosterone receptor antagonist. Mifepristone administration 1 hr before RS prevented the effects of RS on the TOR task in males, but not anxiety. In conclusion, RS has differential effects on recency memory and anxiety, in males and females, which are partly mediated by the effects of corticosterone signalling on synaptic plasticity.
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Glucocorticoides , Receptores de Glucocorticoides , Animales , Corticosterona/farmacología , Femenino , Humanos , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Mifepristona/farmacología , Corteza Prefrontal/metabolismo , Receptores de Glucocorticoides/metabolismo , Caracteres Sexuales , Estrés PsicológicoRESUMEN
The neonatal MK-801 model of schizophrenia has been developed based on the neurodevelopmental and NMDA receptor hypofunction hypotheses of schizophrenia. This animal model is generated with the use of the NMDA receptor antagonist, MK-801, during different temporal windows of postnatal life of rodents leading to behavioral defects in adulthood. However, no studies have examined the role of specific postnatal time periods in the neonatal MK-801 (nMK-801) rodent model and the resulting behavioral and neurobiological effects. Thus, the goal of this study is to systematically investigate the role of NMDA hypofunction, during specific temporal windows in postnatal life on different cognitive and social behavioral paradigms, as well as various neurobiological effects during adulthood. Both female and male mice were injected intraperitoneally (i.p.) with MK-801 during postnatal days 7-14 (p7-14) or 11-15 (p11-15). Control mice were injected with saline during the respective time period. In adulthood, mice were tested in various cognitive and social behavioral tasks. Mice nMK-801-treated on p7-14 show impaired performance in the novel object, object-to-place, and temporal order object recognition (TOR) tasks, the sociability test, and contextual fear extinction. Mice nMK-801-treated on p11-15 only affects performance in the TOR task, the social memory test, and contextual fear extinction. No differences were identified in the expression of NMDA receptor subunits, the synapsin or PSD-95 proteins, either in the prefrontal cortex (PFC) or the hippocampus (HPC), brain regions significantly affected in schizophrenia. The number of parvalbumin (PV)-expressing cells is significantly reduced in the PFC, but not in the HPC, of nMK-801-treated mice on p7-14 compared to their controls. No differences in PV-expressing cells (PFC or HPC) were identified in nMK-801-treated mice on p11-15. We further examined PFC function by recording spontaneous activity in a solution that allows up state generation. We find that the frequency of up states is significantly reduced in both nMK-801-treated mice on p7-14 and p11-15 compared to saline-treated mice. Furthermore, we find adaptations in the gamma and high gamma activity in nMK-801-treated mice. In conclusion, our results show that MK-801 treatment during specific postnatal temporal windows has differential effects on cognitive and social behaviors, as well as on underlying neurobiological substrates.
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Working memory (WM) is the ability to hold on-line and manipulate information. The prefrontal cortex (PFC) is a key brain region involved in WM, while the hippocampus is also involved, particularly, in spatial WM. Although several studies have investigated the neuronal substrates of WM in trained animals, the effects and the mechanisms underlying learning WM tasks have not been explored. In our study, we investigated the effects of learning WM tasks in mice on the function of PFC and hippocampus, by training mice in the delayed alternation task for 9 days (adaptive group). This group was compared to naïve mice (which stayed in their homecage) and mice trained in the alternation procedure only (non-adaptive). Following training, a cohort of mice (Experiment A) was tested in the left-right discrimination task and the reversal learning task, while another cohort (Experiment B) was tested in the attention set-shifting task (AST). The adaptive group performed significantly better in the reversal learning task (Experiment A) and AST (Experiment B), compared to non-adaptive and naïve groups. At the end of the behavioral experiments in Experiment A, field excitatory post-synaptic potential (fEPSP) recordings were performed in PFC and hippocampal brain slices. The adaptive group had enhanced the long-term potentiation (LTP) in the PFC, compared to the other groups. In the hippocampus, both the adaptive and the non-adaptive groups exhibited increased fEPSP compared to the naïve group, but no differences in LTP. In Experiment B, the dendritic spine density was measured, which, in the PFC, was found increased in the adaptive group, compared to the non-adaptive and naïve groups. In the hippocampus, there was an increase in mature dendritic spine density in the adaptive group, compared to the other two groups. Our results indicate a role for LTP and dendritic spine density in learning WM tasks.
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Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Aprendizaje por Laberinto/fisiología , Memoria a Corto Plazo/fisiología , Corteza Prefrontal/fisiología , Animales , Espinas Dendríticas/fisiología , Potenciales Postsinápticos Excitadores , Masculino , RatonesRESUMEN
Working memory refers to a cognitive function that provides temporary storage and manipulation of the information necessary for complex cognitive tasks. Due to its central role in general cognition, several studies have investigated the possibility that training on working memory tasks could improve not only working memory function but also increase other cognitive abilities or modulate other behaviors. This possibility is still highly controversial, with prior studies providing contradictory findings. The lack of systematic approaches and methodological shortcomings complicates this debate even more. This review highlights the impact of working memory training at different ages on humans. Finally, it demonstrates several findings about the neural substrate of training in both humans and experimental animals, including non-human primates and rodents.
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Envejecimiento , Conducta Animal , Cognición , Memoria a Corto Plazo , Corteza Prefrontal/fisiología , Adaptación Fisiológica , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Envejecimiento/psicología , Animales , Niño , Sinapsis Eléctricas/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vías Nerviosas/fisiología , Plasticidad Neuronal , Adulto JovenRESUMEN
Several laboratory animal models have shown that dietary energy restriction (ER) can promote longevity and improve various health aspects in old age. However, whether the entire spectrum of ER-induced short- and long-term physiological and metabolic adaptions is translatable to humans remains to be determined. In this review article, we present recent evidence towards the elucidation of the impact of ER on brain physiology and in age-related neurodegenerative diseases. We also discuss modulatory influences of ER on metabolism and overall on human health, limitations of current experimental designs as well as future perspectives for ER trials in humans. Finally, we summarize signaling pathways and processes known to be affected by both aging and ER with a special emphasis on the link between ER and cellular proteostasis.
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Encéfalo/fisiología , Restricción Calórica/métodos , Envejecimiento Cognitivo/fisiología , Longevidad/fisiología , Enfermedades Neurodegenerativas , Animales , Humanos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/prevención & control , Proteostasis , Transducción de SeñalRESUMEN
Neural stem cell (NSC) grafts have demonstrated significant effects in animal models of spinal cord injury (SCI), yet their clinical translation remains challenging. Significant evidence suggests that the supporting matrix of NSC grafts has a crucial role in regulating NSC effects. Here we demonstrate that grafts based on porous collagen-based scaffolds (PCSs), similar to biomaterials utilized clinically in induced regeneration, can deliver and protect embryonic NSCs at SCI sites, leading to significant improvement in locomotion recovery in an experimental mouse SCI model, so that 12 weeks post-injury locomotion performance of implanted animals does not statistically differ from that of uninjured control animals. NSC-seeded PCS grafts can modulate key processes required to induce regeneration in SCI lesions including enhancing NSC neuronal differentiation and functional integration in vivo, enabling robust axonal elongation, and reducing astrogliosis. Our findings suggest that the efficacy and translational potential of emerging NSC-based SCI therapies could be enhanced by delivering NSC via scaffolds derived from well-characterized clinically proven PCS.
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Human evolution is characterized by brain expansion and up-regulation of genes involved in energy metabolism and synaptic transmission, including the glutamate signaling pathway. Glutamate is the excitatory transmitter of neural circuits sub-serving cognitive functions, with glutamate-modulation of synaptic plasticity being central to learning and memory. GLUD2 is a novel positively-selected human gene involved in glutamatergic transmission and energy metabolism that underwent rapid evolutionary adaptation concomitantly with prefrontal cortex enlargement. Two evolutionary replacements (Gly456Ala and Arg443Ser) made hGDH2 resistant to GTP inhibition and allowed distinct regulation, enabling enhanced enzyme function under high glutamatergic system demands. GLUD2 adaptation may have contributed to unique human traits, but evidence for this is lacking. GLUD2 arose through retro-positioning of a processed GLUD1 mRNA to the X chromosome, a DNA replication mechanism that typically generates pseudogenes. However, by finding a suitable promoter, GLUD2 is thought to have gained expression in nerve and other tissues, where it adapted to their particular needs. Here we generated GLUD2 transgenic (Tg) mice by inserting in their genome a segment of the human X chromosome, containing the GLUD2 gene and its putative promoter. Double IF studies of Tg mouse brain revealed that the human gene is expressed in the host mouse brain in a pattern similar to that observed in human brain, thus providing credence to the above hypothesis. This expressional adaptation may have conferred novel role(s) on GLUD2 in human brain. Previous observations, also in GLUD2 Tg mice, generated and studied independently, showed that the non-redundant function of hGDH2 is markedly activated during early post-natal brain development, contributing to developmental changes in prefrontal cortex similar to those attributed to human divergence. Hence, GLUD2 adaptation may have influenced the evolutionary course taken by the human brain, but understanding the mechanism(s) involved remains challenging.
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Adaptación Fisiológica/fisiología , Encéfalo/fisiología , Evolución Molecular , Glutamato Deshidrogenasa/biosíntesis , Heterocigoto , Animales , Expresión Génica , Glutamato Deshidrogenasa/química , Glutamato Deshidrogenasa/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Estructura Secundaria de Proteína , Cromosoma X/genéticaRESUMEN
Schizophrenia is a debilitating disorder with complex and unclarified etiological factors. Sex differences have been observed in humans but animal models have only focused on male subjects. In this study, we report the establishment of the neurodevelopmental MAM model of schizophrenia in mice and compare the schizotypic-like characteristics and cognitive functions in both sexes. Pregnant mice were injected with methylazoxymethanol acetate (MAM) or saline on gestational day (GD) 16 (MAM-16) or 17 (MAM-17). Female MAM-16, but not MAM-17 treated mice exhibited enhanced hyperlocomotion after acute MK-801 administration, compared to saline treated mice. Male MAM-16, but not MAM-17, treated mice showed reduced pre-pulse inhibition of the acoustic startle reflex. Both male and female MAM-16 and MAM-17 treated mice exhibited smaller hippocampal (HPC) size and thinning of the prefrontal cortex (PFC), but only male MAM-16 treated mice showed decreased parvalbumin expression in HPC and PFC. Similarly, both male and female MAM-16 treated mice displayed impaired contextual fear memory and significantly reduced long-term potentiation (LTP) in the HPC CA1 synapses. However, male, but not female, MAM-16 treated mice exhibited deficits in the delayed alternation task and LTP in layer II PFC synapses. Proteomic analyses of PFC lysates further showed significant MAM- and sex-dependent differences in protein expression regulation. Our results demonstrate that while both male and female mice, prenatally exposed to MAM on GD16, display several core schizophrenia-like deficits and impairments in the hippocampus, only male MAM-treated mice have PFCdependent cognitive deficits.
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Modelos Animales de Enfermedad , Hipocampo/fisiopatología , Corteza Prefrontal/fisiopatología , Esquizofrenia/fisiopatología , Caracteres Sexuales , Animales , Percepción Auditiva/fisiología , Miedo/fisiología , Femenino , Hipocampo/patología , Potenciación a Largo Plazo/fisiología , Masculino , Memoria/fisiología , Acetato de Metilazoximetanol , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Inhibición Prepulso/fisiología , Proteoma , Reflejo de Sobresalto/fisiología , Esquizofrenia/patología , Psicología del EsquizofrénicoRESUMEN
GABAergic (γ-aminobutyric acid) neurons are inhibitory neurons and protect neural tissue from excessive excitation. Cortical GABAergic neurons play a pivotal role for the generation of synchronized cortical network oscillations. Imbalance between excitatory and inhibitory mechanisms underlies many neuropsychiatric disorders and is correlated with abnormalities in oscillatory activity, especially in the gamma frequency range (30-80 Hz). We investigated the functional changes in cortical network activity in response to developmentally reduced inhibition in the adult mouse barrel cortex (BC). We used a mouse model that displays â¼50% fewer cortical interneurons due to the loss of Rac1 protein from Nkx2.1/Cre-expressing cells [Rac1 conditional knockout (cKO) mice], to examine how this developmental loss of cortical interneurons may affect basal synaptic transmission, synaptic plasticity, spontaneous activity, and neuronal oscillations in the adult BC. The decrease in the number of interneurons increased basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks in the Rac1 cKO mouse cortex, decreased long-term potentiation (LTP) in response to tetanic stimulation but did not alter the pair-pulse ratio (PPR). Furthermore, under spontaneous recording conditions, Rac1 cKO brain slices exhibit enhanced sensitivity and susceptibility to emergent spontaneous activity. We also find that this developmental decrease in the number of cortical interneurons results in local neuronal networks with alterations in neuronal oscillations, exhibiting decreased power in low frequencies (delta, theta, alpha) and gamma frequency range (30-80 Hz) with an extra aberrant peak in high gamma frequency range (80-150 Hz). Therefore, our data show that disruption in GABAergic inhibition alters synaptic properties and plasticity, while it additionally disrupts the cortical neuronal synchronization in the adult BC.
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Ondas Encefálicas/fisiología , Corteza Cerebral/citología , Corteza Cerebral/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Interneuronas/fisiología , Animales , Recuento de Células/tendencias , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Red Nerviosa/citología , Red Nerviosa/fisiologíaRESUMEN
The oligodendrocyte maturation process and the transition from the pre-myelinating to the myelinating state are extremely important during development and in pathology. In the present study, we have investigated the role of the cell adhesion molecule CNTN2/TAG-1 on oligodendrocyte proliferation, differentiation, myelination, and function during development and under pathological conditions. With the combination of in vivo, in vitro, ultrastructural, and electrophysiological methods, we have mapped the expression of CNTN2 protein in the oligodendrocyte lineage during the different stages of myelination and its involvement on oligodendrocyte maturation, branching, myelin-gene expression, myelination, and axonal function. The cuprizone model of central nervous system demyelination was further used to assess CNTN2 in pathology. During development, CNTN2 can transiently affect the expression levels of myelin and myelin-regulating genes, while its absence results in reduced oligodendrocyte branching, hypomyelination of fiber tracts and impaired axonal conduction. In pathology, CNTN2 absence does not affect the extent of de- and remyelination. However during remyelination, a novel, CNTN2-independent mechanism is revealed that is able to recluster voltage gated potassium channels (VGKCs) resulting in the improvement of fiber conduction.
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Contactina 2/metabolismo , Enfermedades Desmielinizantes/metabolismo , Oligodendroglía/metabolismo , Animales , Axones/fisiología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Encéfalo/patología , Canales de Calcio/metabolismo , Células Cultivadas , Contactina 2/genética , Cuprizona , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Conducción Nerviosa/fisiología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Oligodendroglía/patología , Técnicas de Cultivo de TejidosRESUMEN
Adolescence is a highly vulnerable period for the emergence of major neuropsychological disorders and is characterized by decreased cognitive control and increased risk-taking behavior and novelty-seeking. The prefrontal cortex (PFC) is involved in the cognitive control of impulsive and risky behavior. Although the PFC is known to reach maturation later than other cortical areas, little information is available regarding the functional changes from adolescence to adulthood in PFC, particularly compared with other primary cortical areas. This study aims to understand the development of PFC-mediated, compared with non-PFC-mediated, cognitive functions. Toward this aim, we performed cognitive behavioral tasks in adolescent and adult mice and subsequently investigated synaptic plasticity in two different cortical areas. Our results showed that adolescent mice exhibit impaired performance in PFC-dependent cognitive tasks compared with adult mice, whereas their performance in non-PFC-dependent tasks is similar to that of adults. Furthermore, adolescent mice exhibited decreased long-term potentiation (LTP) within upper-layer synapses of the PFC but not the barrel cortex. Blocking GABAA receptor function significantly augments LTP in both the adolescent and adult PFC. No change in intrinsic excitability of PFC pyramidal neurons was observed between adolescent and adult mice. Finally, increased expression of the NR2A subunit of the N-methyl-d-aspartate receptors is found only in the adult PFC, a change that could underlie the emergence of LTP. In conclusion, our results demonstrate physiological and behavioral changes during adolescence that are specific to the PFC and could underlie the reduced cognitive control in adolescents. NEW & NOTEWORTHY This study reports that adolescent mice exhibit impaired performance in cognitive functions dependent on the prefrontal cortex but not in cognitive functions dependent on other cortical regions. The current results propose reduced synaptic plasticity in the upper layers of the prefrontal cortex as a cellular correlate of this weakened cognitive function. This decreased synaptic plasticity is due to reduced N-methyl-d-aspartate receptor expression but not due to dampened intrinsic excitability or enhanced GABAergic signaling during adolescence.
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Cognición/fisiología , Plasticidad Neuronal , Neuronas/fisiología , Corteza Prefrontal/fisiología , Corteza Somatosensorial/fisiología , Animales , Conducta Animal , Masculino , Aprendizaje por Laberinto/fisiología , Memoria a Corto Plazo/fisiología , Ratones Endogámicos C57BL , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Reconocimiento en Psicología/fisiología , Corteza Somatosensorial/crecimiento & desarrolloRESUMEN
Autophagy is crucial for neuronal integrity. Loss of key autophagic components leads to progressive neurodegeneration and structural defects in pre- and postsynaptic morphologies. However, the molecular mechanisms regulating autophagy in the brain remain elusive. Similarly, while it is widely accepted that protein turnover is required for synaptic plasticity, the contribution of autophagy to the degradation of synaptic proteins is unknown. Here, we report that BDNF signaling via the tropomyosin receptor kinase B (TrkB) and the phosphatidylinositol-3' kinase (PI3K)/Akt pathway suppresses autophagy in vivo. In addition, we demonstrate that suppression of autophagy is required for BDNF-induced synaptic plasticity and for memory enhancement under conditions of nutritional stress. Finally, we identify three key remodelers of postsynaptic densities as cargo of autophagy. Our results establish autophagy as a pivotal component of BDNF signaling, which is essential for BDNF-induced synaptic plasticity. This molecular mechanism underlies behavioral adaptations that increase fitness in times of scarcity.
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Autofagia , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Plasticidad Neuronal , Transducción de Señal , Animales , Ayuno , Masculino , Ratones Endogámicos C57BL , Neuronas/citología , Neuronas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Prosencéfalo/citología , Prosencéfalo/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor trkB/metabolismoRESUMEN
Smoking represents perhaps the single most important health risk factor and a global contributor to mortality that can unquestionably be prevented. Smoking is responsible for many diseases, including various types of cancer, chronic obstructive pulmonary disease, coronary heart disease, peripheral vascular disease and peptic ulcer, while it adversely affects fetal formation and development. Since smoking habit duration is a critical factor for mortality, the goal of treatment should be its timely cessation and relapse prevention. Drug intervention therapy is an important ally in smoking cessation. Significant positive steps have been achieved in the last few years in the development of supportive compounds. In the present review, we analyze reports studying the role of Corticotropin Releasing Factor (CRF), the principle neuroendocrine mediator of the stress response and its two receptors (CRF1 and CRF2) in the withdrawal phase as well as in the abstinence from nicotine use. Although still in pre-clinical evaluation, therapeutic implications of these data were investigated in order to highlight potential pharmaceutical interventions.