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Severe psychiatric illnesses, for instance schizophrenia, and affective diseases or autism spectrum disorders, have been associated with cognitive impairment and perturbed excitatory-inhibitory balance in the brain. Effects in juvenile mice can elucidate how erythropoietin (EPO) might aid in rectifying hippocampal transcriptional networks and synaptic structures of pyramidal lineages, conceivably explaining mitigation of neuropsychiatric diseases. An imminent conundrum is how EPO restores synapses by involving interneurons. By analyzing ~12,000 single-nuclei transcriptomic data, we generated a comprehensive molecular atlas of hippocampal interneurons, resolved into 15 interneuron subtypes. Next, we studied molecular alterations upon recombinant human (rh)EPO and saw that gene expression changes relate to synaptic structure, trans-synaptic signaling and intracellular catabolic pathways. Putative ligand-receptor interactions between pyramidal and inhibitory neurons, regulating synaptogenesis, are altered upon rhEPO. An array of in/ex vivo experiments confirms that specific interneuronal populations exhibit reduced dendritic complexity, synaptic connectivity, and changes in plasticity-related molecules. Metabolism and inhibitory potential of interneuron subgroups are compromised, leading to greater excitability of pyramidal neurons. To conclude, improvement by rhEPO of neuropsychiatric phenotypes may partly owe to restrictive control over interneurons, facilitating re-connectivity and synapse development.
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Adverse experiences during infancy and adolescence have an important and enduring effect on the brain and are predisposing factors for mental disorders, particularly major depression. This impact is particularly notable in regions with protracted development, such as the prefrontal cortex. The inhibitory neurons of this cortical region are altered by peripubertal stress (PPS), particularly in female mice. In this study we have explored whether the inhibitory circuits of the thalamus are impacted by PPS in male and female mice. This diencephalic structure, as the prefrontal cortex, also completes its development during postnatal life and is affected by adverse experiences. The long-term changes induced by PPS were exclusively found in adult female mice. We have found that PPS increases depressive-like behavior and induces changes in parvalbumin-expressing (PV+) cells of the thalamic reticular nucleus (TRN). We observed reductions in the volume of the TRN, together with those of parameters related to structures/molecules that regulate the plasticity and connectivity of PV+ cells: perineuronal nets, matricellular structures surrounding PV+ neurons, and the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). The expression of the GluN1, but not of GluN2C, NMDA receptor subunit was augmented in the TRN after PPS. An increase in the fluorescence intensity of PV+ puncta was also observed in the synaptic output of TRN neurons in the lateral posterior thalamic nucleus. These results demonstrate that the inhibitory circuits of the thalamus, as those of the prefrontal cortex, are vulnerable to the effects of aversive experiences during early life, particularly in females. This vulnerability is probably related to the protracted development of the TRN and might contribute to the development of psychiatric disorders.
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The estrous cycle is caused by the changing concentration of ovarian hormones, particularly 17ß-estradiol, a hormone whose effect on excitatory circuits has been extensively reported. However, fewer studies have tried to elucidate how this cycle, or this hormone, affects the plasticity of inhibitory networks and the structure of interneurons. Among these cells, somatostatin-expressing O-LM neurons of the hippocampus are especially interesting. They have a role in the modulation of theta oscillations, and they receive direct input from the entorhinal cortex, which place them in the center of hippocampal function. In this study, we report that the expression of polysialylated form of the neural cell adhesion molecule (PSA-NCAM) in the hippocampus, a molecule involved in the plasticity of somatostatin-expressing interneurons in the adult brain, fluctuated through the different stages of the estrous cycle. Likewise, these stages and the expression of PSA-NCAM affected the density of dendritic spines of O-LM cells. We also describe that 17ß-estradiol replacement of adult ovariectomized female mice caused an increase in the perisomatic inhibitory puncta in O-LM interneurons as well as an increase in their axonal bouton density. Interestingly, this treatment also induced a decrease in their dendritic spine density, specifically in O-LM interneurons lacking PSA-NCAM expression. Finally, using an ex vivo real-time assay with entorhinal-hippocampal organotypic cultures, we show that this hormone decreased the dynamics in spinogenesis, altogether highlighting the modulatory effect that 17ß-estradiol has on inhibitory circuits.
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Corteza Entorrinal/fisiología , Estradiol/metabolismo , Hipocampo/fisiología , Interneuronas/fisiología , Red Nerviosa/fisiología , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Ácidos Siálicos/metabolismo , Animales , Células Cultivadas , Espinas Dendríticas/fisiología , Corteza Entorrinal/citología , Corteza Entorrinal/metabolismo , Femenino , Hipocampo/citología , Hipocampo/metabolismo , Interneuronas/metabolismo , Ratones , Ratones Transgénicos , Red Nerviosa/metabolismo , Ovariectomía , Somatostatina/metabolismoRESUMEN
Smoking prevalence in schizophrenia is considerably larger than in general population, playing an important role in early mortality. We compared the polygenic contribution to smoking in schizophrenic patients and controls to assess if genetic factors may explain the different prevalence. Polygenic risk scores (PRSs) for smoking initiation and four genetically correlated traits were calculated in 1108 schizophrenic patients (64.4% smokers) and 1584 controls (31.1% smokers). PRSs for smoking initiation, educational attainment, body mass index and age at first birth were associated with smoking in patients and controls, explaining a similar percentage of variance in both groups. Attention-deficit hyperactivity disorder (ADHD) PRS was associated with smoking only in schizophrenia. This association remained significant after adjustment by psychiatric cross-disorder PRS. A PRS combining all the traits was more explanative than smoking initiation PRS alone, indicating that genetic susceptibility to the other traits plays an additional role in smoking behaviour. Smoking initiation PRS was also associated with schizophrenia in the whole sample, but the significance was lost after adjustment for smoking status. This same pattern was observed in the analysis of specific SNPs at the CHRNA5-CHRNA3-CHRNB4 cluster associated with both traits. Overall, the results indicate that the same genetic factors are involved in smoking susceptibility in schizophrenia and in general population and are compatible with smoking acting, directly or indirectly, as a risk factor for schizophrenia that contributes to the high prevalence of smoking in these patients. The contrasting results for ADHD PRS may be related to higher ADHD symptomatology in schizophrenic patients.
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Esquizofrenia/genética , Fumar Tabaco/genética , Adulto , Trastorno por Déficit de Atención con Hiperactividad/genética , Índice de Masa Corporal , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Herencia Multifactorial , Proteínas del Tejido Nervioso/genética , Fenotipo , Receptores Nicotínicos/genética , Factores de Riesgo , Factores SociodemográficosRESUMEN
Parathyroid hormone-related protein (PTHrP) C-terminal peptides regulate the metabolism of bone cells. PHTrP [107-111] (osteostatin) promotes bone repair in animal models of bone defects and prevents bone erosion in inflammatory arthritis. In addition to its positive effects on osteoblasts, osteostatin may inhibit bone resorption. The aim of this study was to determine the effects of osteostatin on human osteoclast differentiation and function. We used macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL) to induce the osteoclast differentiation of adherent human peripheral blood mononuclear cells. Tartrate-resistant acid phosphatase (TRAP) staining was performed for the detection of the osteoclasts. The function of mature osteoclasts was assessed with a pit resorption assay. Gene expression was evaluated with qRT-PCR, and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) nuclear translocation was studied by immunofluorescence. We observed that osteostatin (100, 250 and 500 nM) decreased the differentiation of osteoclasts in a concentration-dependent manner, but it did not modify the resorptive ability of mature osteoclasts. In addition, osteostatin decreased the mRNA levels of cathepsin K, osteoclast associated Ig-like receptor (OSCAR) and NFATc1. The nuclear translocation of the master transcription factor in osteoclast differentiation NFATc1 was reduced by osteostatin. Our results suggest that the anti-resorptive effects of osteostatin may be dependent on the inhibition of osteoclastogenesis. This study has shown that osteostatin controls human osteoclast differentiation in vitro through the downregulation of NFATc1.
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Resorción Ósea , Ligando RANK , Animales , Resorción Ósea/metabolismo , Diferenciación Celular , Humanos , Leucocitos Mononucleares/metabolismo , Factor Estimulante de Colonias de Macrófagos/metabolismo , Factor Estimulante de Colonias de Macrófagos/farmacología , Factores de Transcripción NFATC/metabolismo , Osteoclastos/metabolismo , Proteína Relacionada con la Hormona Paratiroidea/metabolismo , Fragmentos de Péptidos , Ligando RANK/metabolismo , Ligando RANK/farmacologíaRESUMEN
Parvalbumin-expressing (PV+) interneurons play a key role in the maturation and synchronization of cortical circuitry and alterations in these inhibitory neurons, especially in the medial prefrontal cortex (mPFC), have been found in different psychiatric disorders. The formation of perineuronal nets (PNNs) around many of these interneurons at the end of the critical periods reduces their plasticity and sets their connectivity. Consequently, the presence of PNNs must have an important impact on the synaptic input and the physiology of PV+ cells. In the present study, we have found that in adult male mice, prefrontocortical PV+ cells surrounded by PNNs show higher density of perisomatic excitatory and inhibitory puncta, longer axonal initial segments (AISs), and higher PV expression when compared with PV+ cells lacking PNNs. In order to better understand the impact of PNNs on the connectivity and physiology of PV+ interneurons in the mPFC, we have digested enzymatically these structures and have found a decrease in the density of inhibitory puncta on their perisomatic region but not on the PV+ perisomatic puncta on pyramidal neurons. Moreover, extracellular recordings show that the digestion of PNNs induces a decrease in γ activity, an oscillation dependent on PV+ cells, in the mPFC of anesthetized mice. Our results suggest that the presence of PNNs enwrapping PV+ cells regulates their inhibitory input and has a potent influence on their activity. These results may be relevant for psychiatric research, given the alterations in PNNs, PV+ interneurons and their physiology described in different mental disorders.SIGNIFICANCE STATEMENT Parvalbumin-expressing (PV+) interneurons are surrounded by specializations of the extracellular matrix, the perineuronal nets (PNNs). PNNs regulate the development and plasticity of PV+ cells and, consequently, their presence must influence their synaptic input and physiology. We have found, in the adult prefrontal cortex (PFC), substantial differences in the structure and connectivity of PV+ interneurons depending on the presence of PNNs. The depletion of PNNs from the PFC has also a potent effect on the connectivity of PV+ cells and on neural oscillations that depend on these cells. These findings are relevant to understand the role of PNNs in the adult brain and in certain psychiatric disorders in which alterations in PNNs and PV+ interneurons have been described.
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Matriz Extracelular , Ritmo Gamma/fisiología , Interneuronas/fisiología , Plasticidad Neuronal/fisiología , Corteza Prefrontal/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , ParvalbúminasRESUMEN
The extent of functional maturation and integration of nonproliferative neuronal precursors, becoming neurons in the adult murine piriform cortex, is largely unexplored. We thus questioned whether precursors eventually become equivalent to neighboring principal neurons or whether they represent a novel functional network element. Adult brain neuronal precursors and immature neurons (complex cells) were labeled in transgenic mice (DCX-DsRed and DCX-CreERT2 /flox-EGFP), and their cell fate was characterized with patch clamp experiments and morphometric analysis of axon initial segments. Young (DCX+) complex cells in the piriform cortex of 2- to 4-month-old mice received sparse synaptic input and fired action potentials at low maximal frequency, resembling neonatal principal neurons. Following maturation, the synaptic input detected on older (DCX-) complex cells was larger, but predominantly GABAergic, despite evidence of glutamatergic synaptic contacts. Furthermore, the rheobase current of old complex cells was larger and the maximal firing frequency was lower than those measured in neighboring age-matched principal neurons. The striking differences between principal neurons and complex cells suggest that the latter are a novel type of neuron and new coding element in the adult brain rather than simple addition or replacement for preexisting network components.
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Regulación del Desarrollo de la Expresión Génica/fisiología , Células-Madre Neurales/fisiología , Neurogénesis/fisiología , Corteza Piriforme/fisiología , Animales , Diferenciación Celular/fisiología , Proteína Doblecortina , Ratones , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/metabolismo , Neuronas/fisiología , Neuropéptidos/metabolismo , Corteza Piriforme/metabolismoRESUMEN
PURPOSE: Descriptive psychopathology (DP, sometimes called psychopathology or phenomenology) is the language of psychiatry and is dedicated to the description of mental symptoms. Due to its importance, there is an ongoing case to put it back at the heart of psychiatry and its training. This study seeks to examine the literature on how to train psychiatry residents in DP, including reported educational interventions and educational methods. METHOD: The authors conducted a systematic review following the PRISMA and BEME guidelines to identify literature on how to train psychiatry residents in DP. In May 2019, they searched in Embase, ERIC, PsycINFO, PubMed, Scopus, and Web of Science; of 7,199 initial results, 26 sources were finally included for analysis. The assessment tools were the CRAAP test, Kirkpatrick's 4 levels, and (when applicable) the Medical Education Research Study Quality Instrument (MERSQI). RESULTS: The mean CRAAP score was 38.885 of a possible 50 (SD 0.983; range: 36.859-40.910). Fourteen sources (53.8%) had some kind of training evaluation: Kirkpatrick's level 1 was present in nearly all (13) and was the highest in half of them (7). Regarding the educational interventions, the mean MERSQI score was 10.592 of a possible 18 (SD 2.371; range 9.085-12.098). Lectures were the most widely reported educational method (5); among those in clinical settings, the live supervised interview with feedback was the most usual (4). CONCLUSIONS: Despite its core importance as the language of psychiatry, the literature about training psychiatry residents in DP is scarce and heterogeneous. General lack of training evaluation and ongoing overemphasis on Kirkpatrick's levels 1-2 at the expense of levels 3-4 are causes for concern. During the review process, the authors identified a selection of educational interventions that could serve as the basis for the design of new training efforts in both clinical and nonclinical settings. Topics for future research are also suggested, such as the role of DP in competency-based training frameworks now in vogue and a series of neglected contents. Finally, the combined use of the CRAAP test and the MERSQI may be useful for future systematic reviews in medical education.
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Immature neurons are maintained in cortical regions of the adult mammalian brain. In rodents, many of these immature neurons can be identified in the piriform cortex based on their high expression of early neuronal markers, such as doublecortin (DCX) and the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). This molecule plays critical roles in different neurodevelopmental events. Taking advantage of a DCX-CreERT2/Flox-EGFP reporter mice, we investigated the impact of targeted PSA enzymatic depletion in the piriform cortex on the fate of immature neurons. We report here that the removal of PSA accelerated the final development of immature neurons. This was revealed by a higher frequency of NeuN expression, an increase in the number of cells carrying an axon initial segment (AIS), and an increase in the number of dendrites and dendritic spines on the immature neurons. Taken together, our results demonstrated the crucial role of the PSA moiety in the protracted development of immature neurons residing outside of the neurogenic niches. More studies will be required to understand the intrinsic and extrinsic factors affecting PSA-NCAM expression to understand how the brain regulates the incorporation of these immature neurons to the established neuronal circuits of the adult brain.
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Diferenciación Celular , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Neuronas/citología , Neuronas/metabolismo , Corteza Piriforme/fisiología , Ácidos Siálicos/metabolismo , Animales , Biomarcadores , Proteína Doblecortina , Genes Reporteros , Glicósido Hidrolasas/metabolismo , Inmunofenotipificación , Masculino , Ratones , Transmisión SinápticaRESUMEN
Neurogenesis in the healthy adult murine brain is based on proliferation and integration of stem/progenitor cells and is thought to be restricted to 2 neurogenic niches: the subventricular zone and the dentate gyrus. Intriguingly, cells expressing the immature neuronal marker doublecortin (DCX) and the polysialylated-neural cell adhesion molecule reside in layer II of the piriform cortex. Apparently, these cells progressively disappear along the course of ageing, while their fate and function remain unclear. Using DCX-CreERT2/Flox-EGFP transgenic mice, we demonstrate that these immature neurons located in the murine piriform cortex do not vanish in the course of aging, but progressively resume their maturation into glutamatergic (TBR1+, CaMKII+) neurons. We provide evidence for a putative functional integration of these newly differentiated neurons as indicated by the increase in perisomatic puncta expressing synaptic markers, the development of complex apical dendrites decorated with numerous spines and the appearance of an axonal initial segment. Since immature neurons found in layer II of the piriform cortex are generated prenatally and devoid of proliferative capacity in the postnatal cortex, the gradual maturation and integration of these cells outside of the canonical neurogenic niches implies that they represent a valuable, but nonrenewable reservoir for cortical plasticity.
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Plasticidad de la Célula/genética , Regulación del Desarrollo de la Expresión Génica/genética , Neuronas/fisiología , Corteza Piriforme/citología , Corteza Piriforme/embriología , Células Madre/fisiología , Animales , Bromodesoxiuridina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Embrión de Mamíferos , Glutamato Descarboxilasa/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Neuropéptidos/genética , Neuropéptidos/metabolismo , Ácidos Siálicos/metabolismoRESUMEN
In chronic inflammatory joint diseases, such as rheumatoid arthritis, there is an important bone loss. Parathyroid hormone-related protein (PTHrP) and related peptides have shown osteoinductive properties in bone regeneration models, but there are no data on inflammatory joint destruction. We have investigated whether the PTHrP (107-111) C-terminal peptide (osteostatin) could control the development of collagen-induced arthritis in mice. Administration of osteostatin (80 or 120 µg/kg s.c.) after the onset of disease decreased the severity of arthritis as well as cartilage and bone degradation. This peptide reduced serum IgG2a levels as well as T cell activation, with the downregulation of RORγt+CD4+ T cells and upregulation of FoxP3+CD8+ T cells in lymph nodes. The levels of key cytokines, such as interleukin(IL)-1ß, IL-2, IL-6, IL-17, and tumor necrosis factor-α in mice paws were decreased by osteostatin treatment, whereas IL-10 was enhanced. Bone protection was related to reductions in receptor activator of nuclear factor-κB ligand, Dickkopf-related protein 1, and joint osteoclast area. Osteostatin improves arthritis and controls bone loss by inhibiting immune activation, pro-inflammatory cytokines, and osteoclastogenesis. Our results support the interest of osteostatin for the treatment of inflammatory joint conditions.
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Artritis Experimental/etiología , Artritis Experimental/metabolismo , Citocinas/metabolismo , Susceptibilidad a Enfermedades/inmunología , Mediadores de Inflamación/metabolismo , Osteogénesis , Proteína Relacionada con la Hormona Paratiroidea/farmacología , Fragmentos de Péptidos/farmacología , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Biomarcadores , Biopsia , Huesos/metabolismo , Huesos/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inmunoglobulina G/inmunología , Masculino , Ratones , Peroxidasa/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) are key players in the etiology and therapeutics of schizophrenia. The overactivation of these receptors contributes to mPFC dysfunction. Chronic treatment with D2R agonists modifies the expression of molecules implicated in neuronal structural plasticity, synaptic function, and inhibitory neurotransmission, which are also altered in schizophrenia. These changes are dependent on the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, but nothing is known about the effects of D2R and PSA-NCAM on excitatory neurotransmission and the structure of mPFC pyramidal neurons, two additional features affected in schizophrenia. To evaluate these parameters, we have chronically treated adult rats with PPHT (a D2R agonist) after enzymatic removal of PSA with Endo-N. Both treatments decreased spine density in apical dendrites of pyramidal neurons without affecting their inhibitory innervation. Endo-N also reduced the expression of vesicular glutamate transporter-1. These results indicate that D2R and PSA-NCAM are important players in the regulation of the structural plasticity of mPFC excitatory neurons. This is relevant to our understanding of the neurobiological basis of schizophrenia, in which structural alterations of pyramidal neurons and altered expression of D2R and PSA-NCAM have been found.
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Espinas Dendríticas/efectos de los fármacos , Agonistas de Dopamina/farmacología , Corteza Prefrontal/efectos de los fármacos , Receptores de Dopamina D2/agonistas , Transmisión Sináptica/efectos de los fármacos , Animales , Glicósido Hidrolasas/farmacología , Masculino , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Fenetilaminas/farmacología , Corteza Prefrontal/fisiología , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Ratas , Ratas Sprague-Dawley , Ácidos Siálicos/metabolismoRESUMEN
Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration producing intellectual disability. We have used the Ts65Dn model, that mimics some of the alterations observed in Down Syndrome. This genetic alteration induces an imbalance between excitation and inhibition that has been suggested as responsible for the cognitive impairment present in this syndrome. The hippocampus has a crucial role in memory processing and is an important area to analyze this imbalance. In this report we have analysed, in the hippocampus of Ts65Dn mice, the expression of synaptic markers: synaptophysin, vesicular glutamate transporter-1 and isoform 67 of the glutamic acid decarboxylase; and of different subtypes of inhibitory neurons (Calbindin D-28k, parvalbumin, calretinin, NPY, CCK, VIP and somatostatin). We have observed alterations in the inhibitory neuropil in the hippocampus of Ts65Dn mice. There was an excess of inhibitory puncta and a reduction of the excitatory ones. In agreement with this observation, we have observed an increase in the number of inhibitory neurons in CA1 and CA3, mainly interneurons expressing calbindin, calretinin, NPY and VIP, whereas parvalbumin cell numbers were not affected. These alterations in the number of interneurons, but especially the alterations in the proportion of the different types, may influence the normal function of inhibitory circuits and underlie the cognitive deficits observed in DS.
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Síndrome de Down/patología , Hipocampo/patología , Interneuronas/patología , Animales , Proteínas de Unión al Calcio/metabolismo , Síndrome de Down/genética , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/metabolismo , Neuropéptidos/metabolismo , Neurópilo/patología , Sinapsis/efectos de los fármacos , Sinapsis/metabolismoRESUMEN
Excitatory neurons undergo dendritic spine remodeling in response to different stimuli. However, there is scarce information about this type of plasticity in interneurons. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is a good candidate to mediate this plasticity as it participates in neuronal remodeling and is expressed by some mature cortical interneurons, which have reduced dendritic arborization, spine density, and synaptic input. To study the connectivity of the dendritic spines of interneurons and the influence of PSA-NCAM on their dynamics, we have analyzed these structures in a subpopulation of fluorescent spiny interneurons in the hippocampus of glutamic acid decarboxylase-enhanced green fluorescent protein transgenic mice. Our results show that these spines receive excitatory synapses. The depletion of PSA in vivo using the enzyme Endo-Neuraminidase-N (Endo-N) increases spine density when analyzed 2 days after, but decreases it 7 days after. The dendritic spine turnover was also analyzed in real time using organotypic hippocampal cultures: 24 h after the addition of EndoN, we observed an increase in the apparition rate of spines. These results indicate that dendritic spines are important structures in the control of the synaptic input of hippocampal interneurons and suggest that PSA-NCAM is relevant in the regulation of their morphology and connectivity.
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Espinas Dendríticas/metabolismo , Regulación de la Expresión Génica/fisiología , Interneuronas/ultraestructura , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Molécula L1 de Adhesión de Célula Nerviosa/fisiología , Ácidos Siálicos/metabolismo , Ácidos Siálicos/fisiología , Animales , Animales Recién Nacidos , Calbindina 2/metabolismo , Colecistoquinina/metabolismo , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/ultraestructura , Regulación de la Expresión Génica/efectos de los fármacos , Glutamato Descarboxilasa/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipocampo/citología , Técnicas In Vitro , Interneuronas/efectos de los fármacos , Masculino , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Molécula L1 de Adhesión de Célula Nerviosa/efectos de los fármacos , Neuraminidasa/farmacología , Técnicas de Cultivo de Órganos , Somatostatina/metabolismo , Factores de Tiempo , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
Novel hypotheses suggest that antidepressants, such as the selective serotonin reuptake inhibitor fluoxetine, induce neuronal structural plasticity, resembling that of the juvenile brain, although the underlying mechanisms of this reopening of the critical periods still remain unclear. However, recent studies suggest that inhibitory networks play an important role in this structural plasticity induced by fluoxetine. For this reason we have analysed the effects of a chronic fluoxetine treatment in the hippocampus and medial prefrontal cortex (mPFC) of transgenic mice displaying eGFP labelled interneurons. We have found an increase in the expression of molecules related to critical period plasticity, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), GAD67/65 and synaptophysin, as well as a reduction in the number of parvalbumin expressing interneurons surrounded by perineuronal nets. We have also described a trend towards decrease in the perisomatic inhibitory puncta on pyramidal neurons in the mPFC and an increase in the density of inhibitory puncta on eGFP interneurons. Finally, we have found that chronic fluoxetine treatment affects the structure of interneurons in the mPFC, increasing their dendritic spine density. The present study provides evidence indicating that fluoxetine promotes structural changes in the inhibitory neurons of the adult cerebral cortex, probably through alterations in plasticity-related molecules of neurons or the extracellular matrix surrounding them, which are present in interneurons and are known to be crucial for the development of the critical periods of plasticity in the juvenile brain.
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Antidepresivos de Segunda Generación/farmacología , Corteza Cerebral/citología , Fluoxetina/farmacología , Interneuronas/efectos de los fármacos , Red Nerviosa/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Animales , Recuento de Células , Espinas Dendríticas/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipocampo/citología , Hipocampo/efectos de los fármacos , Interneuronas/citología , Masculino , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Parvalbúminas/genética , Parvalbúminas/metabolismo , Ácidos Siálicos/metabolismo , Factores de Tiempo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
BACKGROUND: Schizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society despite its relatively low prevalence. Sex-based differences have been described in schizophrenia epidemiology, symptomatology and outcomes. Different studies explored the impact of schizophrenia in the brain transcriptome, however we lack a consensus transcriptomic profile that considers sex and differentiates specific cerebral regions. METHODS: We performed a systematic review on bulk RNA-sequencing studies of post-mortem brain samples. Then, we fulfilled differential expression analysis on each study and summarized their results with regions-specific meta-analyses (prefrontal cortex and hippocampus) and a global all-studies meta-analysis. Finally, we used the consensus transcriptomic profiles to functionally characterize the impact of schizophrenia in males and females by protein-protein interaction networks, enriched biological processes and dysregulated transcription factors. RESULTS: We discovered the sex-based dysregulation of 265 genes in the prefrontal cortex, 1.414 genes in the hippocampus and 66 genes in the all-studies meta-analyses. The functional characterization of these gene sets unveiled increased processes related to immune response functions in the prefrontal cortex in male and the hippocampus in female schizophrenia patients and the overexpression of genes related to neurotransmission and synapses in the prefrontal cortex of female schizophrenia patients. Considering a meta-analysis of all brain regions available, we encountered the relative overexpression of genes related to synaptic plasticity and transmission in females and the overexpression of genes involved in organizing genetic information and protein folding in male schizophrenia patients. The protein-protein interaction networks and transcription factors activity analyses supported these sex-based profiles. CONCLUSIONS: Our results report multiple sex-based transcriptomic alterations in specific brain regions of schizophrenia patients, which provides new insight into the role of sex in schizophrenia. Moreover, we unveil a partial overlapping of inflammatory processes in the prefrontal cortex of males and the hippocampus of females.
Schizophrenia is a serious illness characterised by changes in perception, mood and behaviour that profoundly affect patients and society. The frequency, symptoms and progression of schizophrenia are different in women and men, but the biological reason for this is not understood. The identification of disease mechanisms specific in men and women, is relevant because it would allow a better understanding of this pathology, as well as improving the personalisation of diagnoses and treatments for patients. To achieve this goal, in this work we reviewed all available RNA sequencing studies of post-mortem brain samples from women and men affected by schizophrenia. Then, we compared gene expression in each study by sex, and integrated all study results in different brain regions: prefrontal cortex, hippocampus and all-studies. We discovered significant changes between men and women: 265 genes differentially expressed in the prefrontal cortex, 1414 genes in the hippocampus and 66 genes in meta-analyses of all-studies. The study of these genes revealed increased immune response functions in the prefrontal cortex of men and in the hippocampus of women with schizophrenia, as well as increased neurotransmission and synapses in the prefrontal cortex of women with schizophrenia. Our results report multiple gene expression changes in specific brain regions of patients with schizophrenia, providing new insights into the role of sex in schizophrenia.
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Encéfalo , Esquizofrenia , Caracteres Sexuales , Transcriptoma , Esquizofrenia/genética , Esquizofrenia/metabolismo , Humanos , Encéfalo/metabolismo , Femenino , Masculino , Corteza Prefrontal/metabolismoRESUMEN
Down syndrome (DS) is the most common genetic disorder associated with intellectual disability. To study this syndrome, several mouse models have been developed. Among the most common is the Ts65Dn model, which mimics most of the alterations observed in DS. Ts65Dn mice, as humans with DS, show defects in the structure, density, and distribution of dendritic spines in the cerebral cortex and hippocampus. Fasudil is a potent inhibitor of the RhoA kinase pathway, which is involved in the formation and stabilization of dendritic spines. Our study analysed the effect of early chronic fasudil treatment on the alterations observed in the hippocampus of the Ts65Dn model. We observed that treating Ts65Dn mice with fasudil induced an increase in neural plasticity in the hippocampus: there was an increment in the expression of PSA-NCAM and BDNF, in the dendritic branching and spine density of granule neurons, as well as in cell proliferation and neurogenesis in the subgranular zone. Finally, the treatment reduced the unbalance between excitation and inhibition present in this model. Overall, early chronic treatment with fasudil increases cell plasticity and eliminates differences with euploid animals.
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1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Síndrome de Down , Humanos , Ratones , Animales , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/genética , Síndrome de Down/metabolismo , Ratones Transgénicos , Hipocampo/metabolismo , Neuronas/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Different lines of evidence indicate that the structure and physiology of the basal ganglia and the thalamus is disturbed in schizophrenia. However, it is unknown whether the volume and shape of these subcortical structures are affected in schizophrenia with auditory hallucinations (AH), a core positive symptom of the disorder. We took structural MRI from 63 patients with schizophrenia, including 36 patients with AH and 27 patients who had never experienced AH (NAH), and 51 matched healthy controls. We extracted volumes for the left and right thalamus, globus pallidus, putamen, caudate and nucleus accumbens. Shape analysis was also carried out. When comparing to controls, the volume of the right globus pallidus, thalamus, and putamen, was only affected in AH patients. The volume of the left putamen was also increased in individuals with AH, whereas the left globus pallidus was affected in both groups of patients. The shapes of right and left putamen and thalamus were also affected in both groups. The shape of the left globus pallidus was only altered in patients lacking AH, both in comparison to controls and to cases with AH. Lastly, the general PANSS subscale was correlated with the volume of the right thalamus, and the right and left putamen, in patients with AH. We have found volume and shape alterations of many basal ganglia and thalamus in patients with and without AH, suggesting in some cases a possible relationship between this positive symptom and these morphometric alterations.
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Esquizofrenia , Humanos , Esquizofrenia/complicaciones , Esquizofrenia/diagnóstico por imagen , Ganglios Basales/diagnóstico por imagen , Tálamo/diagnóstico por imagen , Putamen/diagnóstico por imagen , Alucinaciones/diagnóstico por imagen , Imagen por Resonancia MagnéticaRESUMEN
Both alterations in neurodevelopment and aversive experiences during childhood and adolescence seem important risk factors for schizophrenia. Animal models reproducing these alterations mimic some of the symptoms, constituting a valid approach to study the etiopathology of this disorder. Among these models, the perinatal injection of N-methyl-d-aspartate receptor antagonists and the postweaning social isolation rearing are among the most widely used. Our aim is to combine them in a "double hit" model, which should produce a wider spectrum of alterations. Lister Hooded rats have been subjected to a single injection of MK-801 at postnatal day 7 and socially isolated from postweaning to adulthood. These animals presented increased body weight gain and volume reductions in their medial prefrontal cortex (mPFC) and hippocampus. They also showed an increased number of activated pyramidal neurons and alterations in the numbers of parvalbumin and calbindin expressing interneurons in the mPFC. The expressions of the polysialylated form of the neural cell adhesion molecule and GAD67 are decreased in the mPFC. The mRNA level of calbindin was decreased, while that of calretinin was increased in the mPFC. The mRNA level of ERbB4, a gene associated to schizophrenia, was also altered in this region. All these structural and neurochemical alterations, specially in cortical inhibitory circuits, are similar to those found in schizophrenic patients and are more numerous than in each of the single models. Consequently, the present "double hit" model may be a better tool to study the neurobiological basis of schizophrenia and to explore new therapeutic approaches.
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Regulación de la Expresión Génica/fisiología , Hipocampo/metabolismo , Hipocampo/patología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Esquizofrenia/patología , Animales , Animales Recién Nacidos , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Maleato de Dizocilpina/administración & dosificación , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Moléculas de Adhesión de Célula Nerviosa/genética , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Embarazo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Esquizofrenia/etiología , Aislamiento SocialRESUMEN
The polysialylated form of the neuronal cell adhesion molecule (PSA-NCAM) is expressed by immature neurons in the amygdala of adult mammals, including non-human primates. In a recent report we have also described the presence of PSA-NCAM-expressing cells in the amygdala of adult humans. Although many of these cells have been classified as mature interneurons, some of them lacked mature neuronal markers, suggesting the presence of immature neurons. We have studied, using immunohistochemistry, the existence and distribution of these immature neurons using post mortem material. We have also analysed the presence of proliferating cells and the association between immature neurons and specialised astrocytes. These parameters have also been studied for comparative purposes in the amygdalae of cats and squirrel monkeys. Our results demonstrate that cells coexpressing doublecortin and PSA-NCAM, but lacking neuronal nuclear antigen expression, were present in the amygdala of adult humans. These cells were organised in elongated clusters, which were located between the white matter of the dorsal hippocampus and the basolateral amygdaloid nucleus. These clusters were not associated with astroglial specialised structures. No cells expressing the proliferative marker Ki67 were observed in the amygdaloid parenchyma, although some of them were found in the vicinity of the lateral ventricle. Immature neurons were also present in the amygdala of squirrel monkeys and cats. These cells also appeared clustered in monkeys, although not as organised as in humans. In cats these cells are scarce, appear isolated and most of the PSA-NCAM-expressing structures corresponded to processes apparently originating from the paleocortical layer II.