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The Polycomb Repressive Complex 2 (PRC2) regulates corticogenesis, yet the consequences of mutations to this epigenetic modifier in the mature brain are poorly defined. Importantly, PRC2 core genes are haploinsufficient and causative of several human neurodevelopmental disorders. To address the role of PRC2 in mature cortical structure and function, we conditionally deleted the PRC2 gene Eed from the developing mouse dorsal telencephalon. Adult homozygotes displayed smaller forebrain structures. Single-nucleus transcriptomics revealed that glutamatergic neurons were particularly affected, exhibiting dysregulated gene expression profiles, accompanied by aberrations in neuronal morphology and connectivity. Remarkably, homozygous mice performed well on challenging cognitive tasks. In contrast, while heterozygous mice did not exhibit clear anatomical or behavioral differences, they displayed dysregulation of neuronal genes and altered neuronal morphology that was strikingly different from homozygous phenotypes. Collectively, these data reveal how alterations to PRC2 function shape the mature brain and reveal a dose-specific role for PRC2 in determining glutamatergic neuron identity.
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Ácido Glutámico , Neurogénesis , Neuronas , Complejo Represivo Polycomb 2 , Animales , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Ratones , Neurogénesis/fisiología , Ácido Glutámico/metabolismo , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/metabolismo , Corteza Cerebral/citología , Masculino , Ratones Endogámicos C57BL , Femenino , Ratones TransgénicosRESUMEN
Biological sex influences decision-making processes in significant ways, differentiating the responses animals choose when faced with a range of stimuli. The neurobiological underpinnings that dictate sex differences in decision-making tasks remains an important open question, yet single-sex studies of males form most studies in behavioural neuroscience. Here we used female and male BALB/c mice on two spatial learning and memory tasks and examined the expression of perineuronal nets (PNNs) and parvalbumin interneurons (PV) in regions correlated with spatial memory. Mice underwent the aversive active place avoidance (APA) task or the appetitive trial-unique nonmatching-to-location (TUNL) touchscreen task. Mice in the APA cohort learnt to avoid the foot-shock and no differences were observed on key measures of the task nor in the number and intensity of PNNs and PV. On the delay but not separation manipulation in the TUNL task, females received more incorrect trials and less correct trials compared to males. Furthermore, females in this cohort exhibited higher intensity PNNs and PV cells in the agranular and granular retrosplenial cortex, compared to males. These data show that female and male mice perform similarly on spatial learning tasks. However, sex differences in neural circuitry may underly differences in making decisions under conditions of uncertainty on an appetitive task. These data emphasise the importance of using mice of both sexes in studies of decision-making neuroscience.
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Interneuronas , Neuronas , Animales , Femenino , Masculino , Ratones , Matriz Extracelular , Interneuronas/metabolismo , Neuronas/metabolismo , Parvalbúminas/metabolismo , Aprendizaje Espacial , IncertidumbreRESUMEN
Background: Corticostriatal circuits, particularly the dorsomedial striatum (DMS) and lateral orbitofrontal cortex, are critical for navigating reversal learning under probabilistic uncertainty. These same areas are implicated in the reversal learning impairments observed in individuals with psychosis as well as their psychotic symptoms, suggesting that they may share a common neurobiological substrate. To address this question, we used psychostimulant exposure and specific activation of the DMS during reversal learning in mice to assess corticostriatal activity. Methods: We used amphetamine treatment to induce psychosis-relevant neurobiology in male mice during reversal learning and to examine pathway-specific corticostriatal activation. To determine the causal role of DMS activity, we used chemogenetics to drive midbrain inputs during a range of probabilistic contingencies. Results: Mice treated with amphetamine showed altered punishment learning, which was associated with decreased shifting after losses and increased perseverative errors after reversals. Reversal learning performance and strategies were dependent on increased activity in lateral orbitofrontal cortex to DMS circuits as well as in the DMS itself. Specific activation of midbrain to DMS circuits also decreased shifting after losses and reversal learning performance. However, these alterations were dependent on the probabilistic contingency. Conclusions: Our work suggests that the DMS plays a multifaceted role in reversal learning. Increasing DMS activity impairs multiple reversal learning processes dependent on the level of uncertainty, confirming its role in the maintenance and selection of incoming cortical inputs. Together, these outcomes suggest that elevated dopamine levels in the DMS could contribute to decision-making impairments in individuals with psychosis.
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Cocaine is one of the most widely used and increasingly popular illicit psychoactive drugs. Unlike other commonly used substances of abuse, cocaine has no pharmacological therapies to treat addiction or aid in rehabilitation. Immunopharmacology has long been touted as a possible avenue to develop effective anticocaine therapies; however, lack of efficacy and designs which are not consistent with simple large-scale production have hindered vaccine translation. We have designed and synthesized a peptide-based anti-cocaine immunogen which we have shown is capable of inducing physiologically relevant immune responses in mice as part of a self-adjuvanting delivery system or in combination with the human-approved commercial adjuvant MF59. We have demonstrated that immunization with the reported vaccine elicits high titers of anti-cocaine IgG and prevents cocaine-induced hyperlocomotion in an in vivo murine model. This peptide-hapten immunogen along with self-adjuvanting liposomal-based delivery system provides a platform for the development of effective anti-drug vaccines.
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Adyuvantes Inmunológicos , Cocaína , Humanos , Animales , Ratones , Adyuvantes Inmunológicos/farmacología , Adyuvantes Farmacéuticos , Haptenos , InmunizaciónRESUMEN
Dopamine levels in the dorsomedial striatum (DMS) are highly dynamic and are thought to underly the encoding of action-outcome associations. Although it is known that amphetamine disrupts the learning that is required for goal-directed action, the role of D1 and D2 receptors in this process has not been established. In this study, we examined the role of D1 and D2 receptor antagonists on learning in response to amphetamine. We used the outcome-specific devaluation task to examine goal-directed action in male C57BL6/J mice treated systemically with either a D1 antagonist (SCH-23990; 0.01 mg/kg) or a D2 antagonist (raclopride; 0.5 mg/kg) and then administered amphetamine (1 mg/kg). The mice were injected repeatedly throughout the instrumental training phase of the task to assess the impact on the learning of action-outcomes, and the subsequent choice test assessing performance of goal-directed action was conducted drug free. Effects of chronic drug administration on locomotor behaviour was assessed before and after the choice test. Treatment during learning with either amphetamine, or the D1 or D2 antagonists, impaired the subsequent performance of goal-directed action. The amphetamine-induced impairment in goal-directed action was reversed in mice treated with raclopride, but not when treated with SCH-23990. By contrast, amphetamine-induced hyperactivity was reversed in mice treated with SCH-23990, but not in mice treated with raclopride. Taken together, these data support the role of a balance of dopamine receptor signalling after amphetamine treatment. While overall D1 receptor availability is necessary to promote learning, in a state of elevated dopamine, modifying D2 receptor function can ameliorate learning deficits.
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Anfetamina , Dopamina , Masculino , Animales , Ratones , Anfetamina/farmacología , Racloprida/farmacología , Condicionamiento Clásico , Ratones Endogámicos C57BL , Receptores de Dopamina D2RESUMEN
The cognitive symptoms of schizophrenia are wide ranging and include impaired goal-directed action. This could be driven by an increase in dopamine transmission in the dorsomedial striatum, a pathophysiological hallmark of schizophrenia. Although commonly associated with psychotic symptoms, dopamine signalling in this region also modulates associative learning that aids in the execution of actions. To gain a better understanding of the role of subcortical dopamine in learning and decision-making, we assessed goal-directed action in male mice using the cross-species outcome-specific devaluation task (ODT). First, we administered systemic amphetamine during training to determine the impact of altered dopaminergic signaling on associative learning. Second, we used pathway-specific chemogenetic approaches to activate the dorsomedial and ventral striatal pathways (that originate in the midbrain) to separately assess learning and performance. Amphetamine treatment during learning led to a dose-dependent impairment in goal-directed action. Activation of both striatal pathways during learning also impaired performance. However, when these pathways were activated during choice, only activation of the ventral pathway impaired goal-directed action. This suggests that elevated transmission in the dorsomedial striatal pathway impairs associative learning processes that guide the goal-directed execution of actions. By contrast, elevated transmission of the ventral striatal pathway disrupts the encoding of outcome values that are important for both associative learning and choice performance. These findings highlight the differential roles of the dorsomedial and ventral inputs into the striatum in goal-directed action and provides insight into how striatal dopamine signaling may contribute to the cognitive problems in those with schizophrenia.
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Dopamina , Objetivos , Ratones , Masculino , Animales , Cuerpo Estriado/fisiología , Neostriado/fisiología , MesencéfaloRESUMEN
Sulfate is essential for healthy foetal growth and neurodevelopment. The SLC13A1 sulfate transporter is primarily expressed in the kidney where it mediates sulfate reabsorption and maintains circulating sulfate levels. To meet foetal demands, maternal sulfate levels increase by twofold in pregnancy via upregulated SLC13A1 expression. Previous studies found hyposulfataemia and reduced renal Slc13a1 mRNA expression in rodent models with either severe vitamin D deficiency or perturbed vitamin D signalling. Here we investigated a mouse model of moderate vitamin D deficiency. However, serum sulfate level and renal Slc13a1 mRNA expression was not decreased by a moderate reduction in circulating vitamin D level. We confirmed that the mouse Slc13a1 5'-flanking region was upregulated by 1,25(OH)2D3 using luciferase assays in a cultured renal OK cell line. These results support the presence of a functional VDRE in the mouse Slc13a1 but suggests that moderate vitamin D deficiency does not impact on sulfate homeostasis. As sulfate biology is highly conserved between rodents and humans, we proposed that human SLC13A1 would be under similar transcriptional regulation by 1,25(OH)2D3. Using an online prediction tool we identified a putative VDRE in the SLC13A1 5'-flanking region but unlike the mouse Slc13a1 sequence, the human sequence did not confer a significant response to 1,25(OH)2D3 in vitro. Overall, this study suggests that moderate vitamin D deficiency may not alter sulfate homeostasis. This needs to be confirmed in humans, particularly during pregnancy when vitamin D and sulfate levels need to be maintained at high levels for healthy maternal and child outcomes.
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Deficiencia de Vitamina D , Vitamina D , Embarazo , Femenino , Niño , Humanos , Ratones , Animales , Regulación de la Expresión Génica , Deficiencia de Vitamina D/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sulfatos/metabolismoRESUMEN
Vitamin D deficiency is prevalent in adults and is associated with cognitive impairment. However, the mechanism by which adult vitamin D (AVD) deficiency affects cognitive function remains unclear. We examined spatial memory impairment in AVD-deficient BALB/c mice and its underlying mechanism by measuring spine density, long term potentiation (LTP), nitric oxide (NO), neuronal nitric oxide synthase (nNOS), and endothelial NOS (eNOS) in the hippocampus. Adult male BALB/c mice were fed a control or vitamin D deficient diet for 20 weeks. Spatial memory performance was measured using an active place avoidance (APA) task, where AVD-deficient mice had reduced latency entering the shock zone compared to controls. We characterised hippocampal spine morphology in the CA1 and dentate gyrus (DG) and made electrophysiological recordings in the hippocampus of behaviourally naïve mice to measure LTP. We next measured NO, as well as glutathione, lipid peroxidation and oxidation of protein products and quantified hippocampal immunoreactivity for nNOS and eNOS. Spine morphology analysis revealed a significant reduction in the number of mushroom spines in the CA1 dendrites but not in the DG. There was no effect of diet on LTP. However, hippocampal NO levels were depleted whereas other oxidation markers were unaltered by AVD deficiency. We also showed a reduced nNOS, but not eNOS, immunoreactivity. Finally, vitamin D supplementation for 10 weeks to AVD-deficient mice restored nNOS immunoreactivity to that seen in in control mice. Our results suggest that lower levels of NO and reduced nNOS immunostaining contribute to hippocampal-dependent spatial learning deficits in AVD-deficient mice.
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Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.
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Trastorno del Espectro Autista/genética , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Trastornos del Neurodesarrollo/genética , Transcriptoma/genética , Animales , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/fisiopatología , Modelos Animales de Enfermedad , Epigénesis Genética , Aseo Animal/fisiología , Humanos , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Trastornos del Neurodesarrollo/metabolismo , Trastornos del Neurodesarrollo/fisiopatología , Fenotipo , Células Sf9 , SpodopteraRESUMEN
Many epidemiological studies have highlighted the link between vitamin D deficiency and schizophrenia. In particular, two prominent studies report an association between neonatal vitamin D deficiency and an increased risk of schizophrenia. In parallel, much has been learnt about the role of vitamin D in the developing central nervous system over the last two decades. Studies in rodent models of developmental vitamin D (DVD)-deficiency describe how brain development is altered leading to a range of neurobiological and behavioral phenotypes of interest to schizophrenia. While glutamate and gamma aminobutyric acid (GABA) systems have been little investigated in these models, alterations in developing dopamine systems are frequently reported. There have been far more studies reporting patients with schizophrenia have an increased risk of vitamin D deficiency compared to well controls. Here we have conducted a systematic review and meta-analysis that basically confirms this association and extends this to first-episode psychosis. However, patients with schizophrenia also have poorer general health, poorer diets, are frequently less active and also have an increased risk of other medical conditions, all factors which reduce circulating vitamin D levels. Therefore, we would urge caution in any causal interpretation of this association. We also summarize the inconsistent results from existing vitamin D supplementation trials in patients with schizophrenia. In respect to animal models of adult vitamin D deficiency, such exposures produce subtle neurochemical alterations and effects on cognition but do not appear to produce behavioral phenotypes of relevance to schizophrenia. We conclude, the hypothesis that vitamin D deficiency during early life may increase the risk of schizophrenia remains plausible and warrants ongoing research.
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Esquizofrenia , Deficiencia de Vitamina D , Animales , Cognición , Dopamina , Humanos , Vitamina D , Deficiencia de Vitamina D/complicacionesRESUMEN
Genetic association studies have identified many factors associated with neurodevelopmental disorders such as autism spectrum disorder (ASD). However, the way these genes shape neuroanatomical structure and connectivity is poorly understood. Recent research has focused on proteins that act as points of convergence for multiple factors, as these may provide greater insight into understanding the biology of neurodevelopmental disorders. USP9X, a deubiquitylating enzyme that regulates the stability of many ASD-related proteins, is one such point of convergence. Loss of function variants in human USP9X lead to brain malformations, which manifest as a neurodevelopmental syndrome that frequently includes ASD, but the underlying structural and connectomic abnormalities giving rise to patient symptoms is unknown. Here, we analyzed forebrain-specific Usp9x knockout mice (Usp9x-/y) to address this knowledge gap. Usp9x-/y mice displayed abnormal communication and social interaction behaviors. Moreover, the absence of Usp9x culminated in reductions to the size of multiple brain regions. Diffusion tensor magnetic resonance imaging revealed deficits in all three major forebrain commissures, as well as long-range hypoconnectivity between cortical and subcortical regions. These data identify USP9X as a key regulator of brain formation and function, and provide insights into the neurodevelopmental syndrome arising as a consequence of USP9X mutations in patients.
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Corteza Cerebral/fisiopatología , Vías Nerviosas/fisiopatología , Neurogénesis/fisiología , Ubiquitina Tiolesterasa/metabolismo , Animales , Conducta Animal , Masculino , Ratones , Ratones NoqueadosRESUMEN
Schizophrenia is characterized by positive, negative and cognitive symptoms. All current antipsychotic treatments feature dopamine-receptor antagonism that is relatively effective at addressing the psychotic (positive) symptoms of schizophrenia. However, there is no clear evidence that these medications improve the negative or cognitive symptoms, which are the greatest predictors of functional outcomes. One of the most robust pathophysiological observations in patients with schizophrenia is increased subcortical dopamine neurotransmission, primarily in the associative striatum. This brain area has an important role in a range of cognitive processes. Dopamine is also known to play a major part in regulating a number of cognitive functions impaired in schizophrenia but much of this research has been focused on cortical dopamine. Emerging research highlights the strong influence subcortical dopamine has on a range of cognitive domains, including attention, reward learning, goal-directed action and decision-making. Nonetheless, the precise role of the associative striatum in the cognitive impairments observed in schizophrenia remains poorly understood, presenting an opportunity to revisit its contribution to schizophrenia. Without a better understanding of the mechanisms underlying cognitive dysfunction, treatment development remains at a standstill. For this reason, improved preclinical animal models are needed if we are to understand the complex relationship between subcortical dopamine and cognition. A range of new techniques are facillitating the discrete manipulation of dopaminergic neurotransmission and measurements of cognitive performance, which can be investigated using a variety of sensitive translatable tasks. This has the potential to aid the successful incorporation of recent clinical research to address the lack of treatment strategies for cognitive symptoms in schizophrenia. This review will give an overview on the current state of research focused on subcortical dopamine and cognition in the context of schizophrenia research. We also discuss future strategies and approaches aimed at improving the translational outcomes for the treatment of cognitive deficits in schizophrenia.
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Vitamin D deficiency is a candidate risk factor for a range of adverse health outcomes. In a genome-wide association study of 25 hydroxyvitamin D (25OHD) concentration in 417,580 Europeans we identify 143 independent loci in 112 1-Mb regions, providing insights into the physiology of vitamin D and implicating genes involved in lipid and lipoprotein metabolism, dermal tissue properties, and the sulphonation and glucuronidation of 25OHD. Mendelian randomization models find no robust evidence that 25OHD concentration has causal effects on candidate phenotypes (e.g. BMI, psychiatric disorders), but many phenotypes have (direct or indirect) causal effects on 25OHD concentration, clarifying the epidemiological relationship between 25OHD status and the health outcomes examined in this study.
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Deficiencia de Vitamina D/genética , Vitamina D/análogos & derivados , Adulto , Anciano , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Reino Unido , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Población Blanca/genéticaRESUMEN
Sotos syndrome is a developmental disorder characterized by a suite of clinical features. In children, the three cardinal features of Sotos syndrome are a characteristic facial appearance, learning disability and overgrowth (height and/or head circumference > 2 SDs above average). These features are also evident in adults with this syndrome. Over 90% of Sotos syndrome patients are haploinsufficient for the gene encoding nuclear receptor-binding Su(var)3-9, Enhancer-of-zesteand Trithorax domain-containing protein 1 (NSD1). NSD1 is a histone methyltransferase that catalyzes the methylation of lysine residue 36 on histone H3. However, although the symptomology of Sotos syndrome is well established, many aspects of NSD1 biology remain unknown. Here, we assessed the expression of Nsd1 within the mouse brain, and showed a predominantly neuronal pattern of expression for this histone-modifying factor. We also generated a mouse strain lacking one allele of Nsd1 and analyzed morphological and behavioral characteristics in these mice, showing behavioral characteristics reminiscent of some of the deficits seen in Sotos syndrome patients.
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Corteza Cerebral/patología , N-Metiltransferasa de Histona-Lisina/genética , Síndrome de Sotos/genética , Animales , Corteza Cerebral/metabolismo , Femenino , Heterocigoto , N-Metiltransferasa de Histona-Lisina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Síndrome de Sotos/patologíaRESUMEN
Intellectual disability (ID) and autism spectrum disorder (ASD) are two of the most common neurodevelopmental disorders. Both disorders are extremely heterogenous, and only ~ 40% of reported cases have so far been attributed to genetic mutations. Of the many cellular processes that are affected, the ubiquitin system (UbS) is of particular relevance in that it can rapidly regulate multiple signaling cascades simultaneously. The UbS is a post-translational modification process that revolves around the covalent attachment of a ubiquitin moiety to a substrate, thereby influencing different elements of protein biology, including trafficking, signal transduction, and degradation. Importantly, the UbS has been implicated in regulating multiple pathophysiological pathways related to ASD and ID. This review will discuss how the UbS acts as major signaling hub in the pathogenesis of ASD and ID, raising the prospect of treating broader patient cohorts by targeting the UbS as a common point of convergence of various mutations.
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Trastorno del Espectro Autista/metabolismo , Discapacidad Intelectual/metabolismo , Procesamiento Proteico-Postraduccional , Ubiquitina/metabolismo , Ubiquitinación/fisiología , Adolescente , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Niño , Femenino , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Masculino , Procesamiento Proteico-Postraduccional/genética , Procesamiento Proteico-Postraduccional/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/fisiología , Factor de Crecimiento Transformador beta/fisiología , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , Ubiquitinación/genética , Vía de Señalización WntRESUMEN
Variants in the ANK3 gene encoding ankyrin-G are associated with neurodevelopmental disorders, including intellectual disability, autism, schizophrenia, and bipolar disorder. However, no upstream regulators of ankyrin-G at synapses are known. Here, we show that ankyrin-G interacts with Usp9X, a neurodevelopmental-disorder-associated deubiquitinase (DUB). Usp9X phosphorylation enhances their interaction, decreases ankyrin-G polyubiquitination, and stabilizes ankyrin-G to maintain dendritic spine development. In forebrain-specific Usp9X knockout mice (Usp9X-/Y), ankyrin-G as well as multiple ankyrin-repeat domain (ANKRD)-containing proteins are transiently reduced at 2 but recovered at 12 weeks postnatally. However, reduced cortical spine density in knockouts persists into adulthood. Usp9X-/Y mice display increase of ankyrin-G ubiquitination and aggregation and hyperactivity. USP9X mutations in patients with intellectual disability and autism ablate its catalytic activity or ankyrin-G interaction. Our data reveal a DUB-dependent mechanism of ANKRD protein homeostasis, the impairment of which only transiently affects ANKRD protein levels but leads to persistent neuronal, behavioral, and clinical abnormalities.
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Repetición de Anquirina/fisiología , Espinas Dendríticas/fisiología , Homeostasis/fisiología , Proteostasis/fisiología , Ubiquitina Tiolesterasa/metabolismo , Animales , Células Cultivadas , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neurogénesis/fisiología , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Ubiquitina Tiolesterasa/química , Ubiquitina Tiolesterasa/genéticaRESUMEN
Schizophrenia has been associated with a range of genetic and environmental risk factors. Here we explored a link between two risk factors that converge on a shared neurobiological pathway. Recent genome-wide association studies (GWAS) have identified risk variants in genes that code for L-type voltage-gated calcium channels (L-VGCCs), while epidemiological studies have found an increased risk of schizophrenia in those with neonatal vitamin D deficiency. The active form of vitamin D (1,25(OH)2D) is a secosteroid that rapidly modulates L-VGCCs via non-genomic mechanisms in a range of peripheral tissues, though its non-genomic effects within the brain remain largely unexplored. Here we used calcium imaging, electrophysiology and molecular biology to determine whether 1,25(OH)2D non-genomically modulated L-VGCCs in the developing prefrontal cortex, a region widely implicated in schizophrenia pathophysiology. Wide-field Ca2+ imaging revealed that physiological concentrations of 1,25(OH)2D rapidly enhanced activity-dependent somatic Ca2+ levels in a small subset of neurons in the developing PFC, termed vitamin D-responsive neurons (VDRNs). Somatic nucleated patch recordings revealed a rapid, 1,25(OH)2D-evoked increase in high-voltage-activated (HVA) Ca2+ currents. Enhanced activity-dependent Ca2+ levels were mediated by L-VGCC but not associated with any changes to Cacna1c (L-VGCC pore-forming subunit) mRNA expression. Since L-VGCC activity is critical to healthy neurodevelopment, these data suggest that suboptimal concentrations of 1,25(OH)2D could alter brain maturation through modulation of L-VGCC signalling and as such may provide a parsimonious link between epidemiologic and genetic risk factors for schizophrenia.
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Canales de Calcio Tipo L/fisiología , Señalización del Calcio , Neurogénesis/fisiología , Corteza Prefrontal/crecimiento & desarrollo , Vitamina D/análogos & derivados , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Neuronas/fisiología , Corteza Prefrontal/fisiología , Vitamina D/fisiologíaRESUMEN
Developmental vitamin D (DVD) deficiency is a risk factor for schizophrenia. In rodents we show that DVD-deficiency alters brain development and produces behavioral phenotypes in the offspring of relevance to the positive symptoms of schizophrenia. The aims of this study are to examine behavioral phenotypes specific to the cognitive and negative symptoms of schizophrenia in this model, and to vary the duration of vitamin D deficiency during gestation and beyond birth. We hypothesize that a longer duration of DVD-deficiency would result in greater behavioral impairments. Female vitamin D-deficient Sprague Dawley dams were mated at 10 weeks of age. Dietary vitamin D was reintroduced to dams and/or pups at different developmental time-points: Conception, Birth, Post-natal day (PND) 6 and PND21. Adult male and female offspring were assessed on a battery of behavioral tests, including sucrose preference, open field, novel object recognition (NOR), social approach and social novelty. We find that all windows of DVD-deficiency impaired NOR a cognitive measure that requires intact recognition memory. Sucrose consumption, social approach and social memory negative symptom-like phenotypes were unaffected by any maternal dietary manipulation. In addition, contrary to our hypothesis, we find that rats in the Conception group, that is the shortest duration of vitamin D deficiency, demonstrate increased locomotor activity, and decreased interaction time with novel objects. These findings have implications for the increasing number of studies examining the preclinical consequences of maternal vitamin D deficiency, and continue to suggest that adequate levels of maternal vitamin D are required for normal brain development.
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Conducta Animal , Encéfalo/crecimiento & desarrollo , Efectos Tardíos de la Exposición Prenatal , Reconocimiento en Psicología , Conducta Social , Deficiencia de Vitamina D/complicaciones , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Cognición , Conducta Alimentaria , Femenino , Edad Gestacional , Locomoción , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Embarazo , Ratas Sprague-Dawley , Deficiencia de Vitamina D/metabolismo , Deficiencia de Vitamina D/fisiopatología , Deficiencia de Vitamina D/psicologíaRESUMEN
Converging evidence from human and animal studies support an association between vitamin D deficiency and cognitive impairment. Previous studies have shown that hippocampal volume is reduced in adults with vitamin D deficiency as well as in a range of disorders, such as schizophrenia. The aim of the current study was to examine the effect of adult vitamin D (AVD) deficiency on hippocampal-dependent spatial learning, and hippocampal volume and connectivity in healthy adult mice. Ten-week-old male BALB/c mice were fed a control (vitamin D 1500 IU/kg) or vitamin D-depleted (vitamin D 0 IU/kg) diet for a minimum of 10 weeks. The mice were then tested for hippocampal-dependent spatial learning using active place avoidance (APA) and on tests of muscle and motor coordination (rotarod and grip strength). The mice were perfused and brains collected to acquire ex vivo structural and diffusion-weighted images using a 16.4 T MRI scanner. We also performed immunohistochemistry to quantify perineuronal nets (PNNs) and parvalbumin (PV) interneurons in various brain regions. AVD-deficient mice had a lower latency to enter the shock zone on APA, compared to control mice, suggesting impaired hippocampal-dependent spatial learning. There were no differences in rotarod or grip strength, indicating that AVD deficiency did not have an impact on muscle or motor coordination. AVD deficiency did not have an impact on hippocampal volume. However, AVD-deficient mice displayed a disrupted network centred on the right hippocampus with abnormal connectomes among 29 nodes. We found a reduction in PNN positive cells, but no change in PV, centred on the hippocampus. Our results provide compelling evidence to show that AVD deficiency in otherwise healthy adult mice may play a key role in hippocampal-dependent learning and memory formation. We suggest that the spatial learning deficits could be due to the disruption of right hippocampal structural connectivity.
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Deficiencia de Ácido Ascórbico/complicaciones , Deficiencia de Ácido Ascórbico/patología , Hipocampo/fisiopatología , Discapacidades para el Aprendizaje/etiología , Vías Nerviosas/fisiopatología , Análisis de Varianza , Animales , Deficiencia de Ácido Ascórbico/diagnóstico por imagen , Reacción de Prevención/fisiología , Conectoma , Toma de Decisiones Asistida por Computador , Modelos Animales de Enfermedad , Hipocampo/patología , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos BALB C , Músculo Esquelético/fisiopatología , Vías Nerviosas/diagnóstico por imagen , Parvalbúminas/metabolismo , Lectinas de Plantas/metabolismo , Trastornos Psicomotores/etiología , Receptores N-Acetilglucosamina/metabolismoRESUMEN
Over a billion people worldwide are affected by vitamin D deficiency. Although vitamin D deficiency is associated with impaired cognition, the mechanisms mediating this link are poorly understood. The extracellular matrix (ECM) has now emerged as an important participant of synaptic plasticity and a new hypothesis is that vitamin D may interact with aggregates of the ECM, perineuronal nets (PNNs), to regulate brain plasticity. Dysregulation of PNNs caused by vitamin D deficiency may contribute to the presentation of cognitive deficits. Understanding the molecular mechanisms underpinning the role of vitamin D in brain plasticity and cognition could help identify ways to treat cognitive symptoms in schizophrenia and other neuropsychiatric conditions.