Sergiu P. Pasca

All Publications

• Personalized Human Cortical Spheroids. American journal of psychiatry Pasca, S. P. 2016; 173 (4): 332-333

  View details for DOI 10.1176/appi.ajp.2016.16020133

  View details for PubMedID 27035533

• A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients. eLife Sun, Y., Paşca, S. P., Portmann, T., Goold, C., Worringer, K. A., Guan, W., Chan, K. C., Gai, H., Vogt, D., Chen, Y. J., Mao, R., Chan, K., Rubenstein, J. L., Madison, D. V., Hallmayer, J., Froehlich-Santino, W. M., Bernstein, J. A., Dolmetsch, R. E. 2016; 5

  Abstract

  Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Nav1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons.

  View details for DOI 10.7554/eLife.13073

  View details for PubMedID 27458797

• Neural Differentiation in the Third Dimension: Generating a Human Midbrain. Cell stem cell Marton, R. M., Paşca, S. P. 2016; 19 (2): 145-6

  Abstract

  In recent years, technological improvements in three-dimensional (3D) culture systems have enabled the generation of organoids or spheroids representing a variety of tissues, including the brain. In this issue of Cell Stem Cell, Jo et al. (2016) describe a 3D culture model of the human midbrain containing dopaminergic neurons and neuromelanin.

  View details for DOI 10.1016/j.stem.2016.07.017

  View details for PubMedID 27494668

• Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nature Biotechnology Deverman, B. E., Pravdo, P. L., Simpson, B. P., Kumar, S. R., Chan, K. Y., Banerjee, A., Wu, W., Yang, B., Huber, N., Pasca, S., Gradinaru, V. 2016; 34 (2): 204-9

  View details for DOI 10.1038/nbt.3440

• Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nature methods Pasca, A. M., Sloan, S. A., Clarke, L. E., Tian, Y., Makinson, C. D., Huber, N., Kim, C. H., Park, J., O'Rourke, N. A., Nguyen, K. D., Smith, S. J., Huguenard, J. R., Geschwind, D. H., Barres, B. A., Pasca, S. P. 2015; 12 (7): 671-678

  Abstract

  The human cerebral cortex develops through an elaborate succession of cellular events that, when disrupted, can lead to neuropsychiatric disease. The ability to reprogram somatic cells into pluripotent cells that can be differentiated in vitro provides a unique opportunity to study normal and abnormal corticogenesis. Here, we present a simple and reproducible 3D culture approach for generating a laminated cerebral cortex-like structure, named human cortical spheroids (hCSs), from pluripotent stem cells. hCSs contain neurons from both deep and superficial cortical layers and map transcriptionally to in vivo fetal development. These neurons are electrophysiologically mature, display spontaneous activity, are surrounded by nonreactive astrocytes and form functional synapses. Experiments in acute hCS slices demonstrate that cortical neurons participate in network activity and produce complex synaptic events. These 3D cultures should allow a detailed interrogation of human cortical development, function and disease, and may prove a versatile platform for generating other neuronal and glial subtypes in vitro.

  View details for DOI 10.1038/nmeth.3415

  View details for PubMedID 26005811

• Generating Human Neurons In Vitro and Using Them to Understand Neuropsychiatric Disease ANNUAL REVIEW OF NEUROSCIENCE, VOL 37 Pasca, S. P., Panagiotakos, G., Dolmetsch, R. E. 2014; 37: 479-?

  Abstract

  Recent advances in cell reprogramming enable investigators to generate pluripotent stem cells from somatic cells. These induced pluripotent cells can subsequently be differentiated into any cell type, making it possible for the first time to obtain functional human neurons in the lab from control subjects and patients with psychiatric disorders. In this review, we survey the progress made in generating various neuronal subtypes in vitro, with special emphasis on the characterization of these neurons and the identification of unique features of human brain development in a dish. We also discuss efforts to uncover neuronal phenotypes from patients with psychiatric disease and prospects for the use of this platform for drug development.

  View details for DOI 10.1146/annurev-neuro-062012-170328

  View details for Web of Science ID 000348454500024

  View details for PubMedID 25002278

• Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons NATURE NEUROSCIENCE Krey, J. F., Pasca, S. P., Shcheglovitov, A., Yazawa, M., Schwemberger, R., Rasmusson, R., Dolmetsch, R. E. 2013; 16 (2): 201-209

  Abstract

  L-type voltage gated calcium channels have an important role in neuronal development by promoting dendritic growth and arborization. A point mutation in the gene encoding Ca(V)1.2 causes Timothy syndrome, a neurodevelopmental disorder associated with autism spectrum disorders (ASDs). We report that channels with the Timothy syndrome alteration cause activity-dependent dendrite retraction in rat and mouse neurons and in induced pluripotent stem cell (iPSC)-derived neurons from individuals with Timothy syndrome. Dendrite retraction was independent of calcium permeation through the mutant channel, was associated with ectopic activation of RhoA and was inhibited by overexpression of the channel-associated GTPase Gem. These results suggest that Ca(V)1.2 can activate RhoA signaling independently of Ca(2+) and provide insights into the cellular basis of Timothy syndrome and other ASDs.

  View details for DOI 10.1038/nn.3307

  View details for Web of Science ID 000314260200017

  View details for PubMedID 23313911

• Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome NATURE MEDICINE Pasca, S. P., Portmann, T., Voineagu, I., Yazawa, M., Shcheglovitov, A., Pasca, A. M., Cord, B., Palmer, T. D., Chikahisa, S., Nishino, S., Bernstein, J. A., Hallmayer, J., Geschwind, D. H., Dolmetsch, R. E. 2011; 17 (12): 1657-U176

  Abstract

  Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Ca(v)1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca(2+)) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons. In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker. These findings provide strong evidence that Ca(v)1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome.

  View details for DOI 10.1038/nm.2576

  View details for Web of Science ID 000297978000039

  View details for PubMedID 22120178

• Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome GENOME MEDICINE Tian, Y., Voineagu, I., Pasca, S. P., Won, H., Chandran, V., Horvath, S., Dolmetsch, R. E., Geschwind, D. H. 2014; 6

  View details for DOI 10.1186/s13073-014-0075-5

  View details for Web of Science ID 000344567900001

• A promoter in the coding region of the calcium channel gene CACNA1C generates the transcription factor CCAT. PloS one Gomez-Ospina, N., Panagiotakos, G., Portmann, T., Pasca, S. P., Rabah, D., Budzillo, A., Kinet, J. P., Dolmetsch, R. E. 2013; 8 (4)

  Abstract

  The C-terminus of the voltage-gated calcium channel Cav1.2 encodes a transcription factor, the calcium channel associated transcriptional regulator (CCAT), that regulates neurite extension and inhibits Cav1.2 expression. The mechanisms by which CCAT is generated in neurons and myocytes are poorly understood. Here we show that CCAT is produced by activation of a cryptic promoter in exon 46 of CACNA1C, the gene that encodes CaV1.2. Expression of CCAT is independent of Cav1.2 expression in neuroblastoma cells, in mice, and in human neurons derived from induced pluripotent stem cells (iPSCs), providing strong evidence that CCAT is not generated by cleavage of CaV1.2. Analysis of the transcriptional start sites in CACNA1C and immune-blotting for channel proteins indicate that multiple proteins are generated from the 3' end of the CACNA1C gene. This study provides new insights into the regulation of CACNA1C, and provides an example of how exonic promoters contribute to the complexity of mammalian genomes.

  View details for DOI 10.1371/journal.pone.0060526

  View details for PubMedID 23613729

• Motor abnormalities as a putative endophenotype for Autism Spectrum Disorders. Frontiers in integrative neuroscience Esposito, G., Pasca, S. P. 2013; 7: 43-?

  Abstract

  Autism Spectrum Disorders (ASDs) represent a complex group of behaviorally defined conditions with core deficits in social communication and the presence of repetitive and restrictive behaviors. To date, neuropathological studies have failed to identify pathognomonic cellular features for ASDs and there remains a fundamental disconnection between the complex clinical aspects of ASDs and the underlying neurobiology. Although not listed among the core diagnostic domains of impairment in ASDs, motor abnormalities have been consistently reported across the spectrum. In this perspective article, we summarize the evidence that supports the use of motor abnormalities as a putative endophenotype for ASDs. We argue that because these motor abnormalities do not directly depend on social or linguistic development, they may serve as an early disease indicator. Furthermore, we propose that stratifying patients based on motor development could be useful not only as an outcome predictor and in identifying more specific treatments for different ASDs categories, but also in exposing neurobiological mechanisms.

  View details for DOI 10.3389/fnint.2013.00043

  View details for PubMedID 23781177

• Surround modulation of neuronal responses in V1 is as stable over time as responses to direct stimulation of receptive fields CORTEX Pasca, S. P., Singer, W., Nikolic, D. 2010; 46 (9): 1199-1203

  Abstract

  In the primary visual cortex (V1) the modulation of neuronal responses by surround stimuli displays considerable variability. At present, it is not known whether this variability across neurons is due to temporal instability or to neuron-specific differences. We explored this question in the cat visual cortex by making multi-channel recordings while repeatedly presenting surround gratings of collinear and orthogonal orientation to the centre stimulus for a period of 96 h. Our results indicate that surround modulation is temporally stable to about the same degree as the responses evoked by the centre stimuli. The results support the notion that the mechanisms of surround modulation exhibit a high degree of stability and play an important role in the modulation of cortical responses.

  View details for DOI 10.1016/j.cortex.2010.05.003

  View details for Web of Science ID 000282561600014

  View details for PubMedID 20557882

• Paraoxonase 1 activities and polymorphisms in autism spectrum disorders JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Pasca, S. P., Dronca, E., Nemes, B., Kaucsar, T., Endreffy, E., Iftene, F., Benga, I., Cornean, R., Dronca, M. 2010; 14 (3): 600-607

  Abstract

  Autism spectrum disorders (ASD) comprise a complex and heterogeneous group of conditions of unknown aetiology, characterized by significant disturbances in social, communicative and behavioural functioning. Recent studies suggested a possible implication of the high-density lipoprotein associated esterase/lactonase paraoxonase 1 (PON1) in ASD. In the present study, we aimed at investigating the PON1 status in a group of 50 children with ASD as compared to healthy age and sex matched control participants. We evaluated PON1 bioavailability (i.e. arylesterase activity) and catalytic activity (i.e. paraoxonase activity) in plasma using spectrophotometric methods and the two common polymorphisms in the PON1 coding region (Q192R, L55M) by employing Light Cycler real-time PCR. We found that both PON1 arylesterase and PON1 paraoxonase activities were decreased in autistic patients (respectively, P < 0.001, P < 0.05), but no association with less active variants of the PON1 gene was found. The PON1 phenotype, inferred from the two-dimensional enzyme analysis, had a similar distribution in the ASD group and the control group. In conclusion, both the bioavailability and the catalytic activity of PON1 are impaired in ASD, despite no association with the Q192R and L55M polymorphisms in the PON1 gene and a normal distribution of the PON1 phenotype.

  View details for DOI 10.1111/j.1582-4934.2008.00414.x

  View details for Web of Science ID 000276950100011

  View details for PubMedID 18624774

• One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Pasca, S. P., Dronca, E., Kaucsar, T., Craciun, E. C., Endreffy, E., Ferencz, B. K., Iftene, F., Benga, I., Cornean, R., Banerjee, R., Dronca, M. 2009; 13 (10): 4229-4238

  Abstract

  Autism spectrum disorders (ASDs), which include the prototypic autistic disorder (AD), Asperger's syndrome (AS) and pervasive developmental disorders not otherwise specified (PDD-NOS), are complex neurodevelopmental conditions of unknown aetiology. The current study investigated the metabolites in the methionine cycle, the transsulphuration pathway, folate, vitamin B(12) and the C677T polymorphism of the MTHFR gene in three groups of children diagnosed with AD (n= 15), AS (n= 5) and PDD-NOS (n= 19) and their age- and sex-matched controls (n= 25). No metabolic disturbances were seen in the AS patients, while in the AD and PDD-NOS groups, lower plasma levels of methionine (P= 0.01 and P= 0.03, respectively) and alpha-aminobutyrate were observed (P= 0.01 and P= 0.001, respectively). Only in the AD group, plasma cysteine (P= 0.02) and total blood glutathione (P= 0.02) were found to be reduced. Although there was a trend towards lower levels of serine, glycine, N, N-dimethylglycine in AD patients, the plasma levels of these metabolites as well as the levels of homocysteine and cystathionine were not statistically different in any of the ASDs groups. The serum levels of vitamin B(12) and folate were in the normal range. The results of the MTHFR gene analysis showed a normal distribution of the C677T polymorphism in children with ASDs, but the frequency of the 677T allele was slightly more prevalent in AD patients. Our study indicates a possible role for the alterations in one carbon metabolism in the pathophysiology of ASDs and provides, for the first time, preliminary evidence for metabolic and genetic differences between clinical subtypes of ASDs.

  View details for DOI 10.1111/j.1582-4934.2008.00463.x

  View details for Web of Science ID 000274181900015

  View details for PubMedID 19267885

• Vomiting is not an adaption for glaucoma (and Darwinian medicine is difficult) MEDICAL HYPOTHESES Pasca, S. P., Nesse, R. M. 2008; 71 (3): 472-473

  View details for DOI 10.1016/j.mehy.2008.04.009

  View details for Web of Science ID 000258641800040

  View details for PubMedID 18513879

• Serum paraoxonase 1 activities and homocysteinemia in hemodialysis patients CLINICAL CHEMISTRY AND LABORATORY MEDICINE Dronca, M., Pasca, S. P., Nemes, B., Vlase, L., Vladutiu, D. 2008; 46 (6): 880-881

  View details for DOI 10.1515/CCLM.2008.164

  View details for Web of Science ID 000257542800023

  View details for PubMedID 18601616

• Behavioral effects of corpus callosum transection and environmental enrichment in adult rats BEHAVIOURAL BRAIN RESEARCH Miu, A. C., Heilman, R. M., Pasca, S. P., Stefan, C. A., Spanu, F., Vasiu, R., Olteanu, A. I., Miclea, M. 2006; 172 (1): 135-144

  Abstract

  A common assumption about the corpus callosum transection (CCX) is that it only affects behaviors heavily relying on interhemispheric communication. However, cerebral laterality is ubiquitous across motor and perceptual, cognitive and emotional domains, and the corpus callosum is important for its establishment. Several recent studies showed that the partial denervation of the sensorimotor isocortex through CCX derepressed neural growth processes that were sensitive to motor demand (experience-dependent neural plasticity). We investigated whether the facilitatory effects of CCX on cortical neural plasticity, shaped by differential housing, extended beyond the motor domain. Adult rats were housed in enriched (EE), standard (SE) or impoverished environments (IE) for 10 weeks, that is, 2 weeks before they underwent CCX or sham surgery, and, then, 8 weeks throughout the experiments. After they recovered from surgery, the behavioral performance of rats was tested using open-field, spontaneous alternation in the T-maze, paw preference, Morris water maze, and tone fear conditioning. The results indicated that the effects of CCX and housing on open-field behavior were independent, with CCX increasing the time spent in the center of the field at the beginning of the observation (i.e., emotionality), and EE and IE increasing rearing (emotionality) and reducing teeth-chattering (habituation), respectively. CCX reduced the frequency of spontaneous alternation, denoting spatial working memory deficits, while housing did not influence this performance. Neither CCX, nor housing significantly affected paw preference lateralization, although CCX was associated with a leftward bias in paw preference. In the Morris water maze, housing had effects on spatial acquisition, while CCX reduced activity, without interfering with spatial memory. CCX did not influence tone fear conditioning, but context fear conditioning seemed to benefit from EE. We conclude that CCX in adult rats has subtle, but specific behavioral effects pertaining to emotionality, spatial working memory, and, possibly, aversively motivated exploration, and these effects are either independent or only peripherally interact with the effects of housing.

  View details for DOI 10.1016/j.bbr.2006.05.007

  View details for Web of Science ID 000239683800016

  View details for PubMedID 16764947

• High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism LIFE SCIENCES Pasca, S. P., Nemes, B., Vlase, L., Gagyi, C. E., Dronca, E., Miu, A. C., Dronca, M. 2006; 78 (19): 2244-2248

  Abstract

  Autism is a behaviorally defined disorder of unknown etiology that is thought to be influenced by genetic and environmental factors. High levels of homocysteine and oxidative stress are generally associated with neuropsychiatric disorders. The purpose of this study was to compare the level of homocysteine and other biomarkers in children with autism to corresponding values in age-matched healthy children. We measured total homocysteine (tHcy), vitamin B(12), paraoxonase and arylesterase activities of human paraoxonase 1 (PON1) in plasma and glutathione peroxidase (GPx) activity in erythrocytes from 21 children: 12 with autism (age: 8.29 +/- 2.76 years) and 9 controls (age: 8.33 +/- 1.82 years). We found statistically significant differences in tHcy levels and in arylesterase activity of PON1 in children with autism compared to the control group: 9.83 +/- 2.75 vs. 7.51 +/- 0.93 micromol/L (P < or =0.01) and 72.57 +/- 11.73 vs. 81.83 +/- 7.39 kU/L (P < or =0.005). In the autistic group there was a strong negative correlation between tHcy and GPx activity and the vitamin B(12) level was low or suboptimal. In conclusion, our study shows that in children with autism there are higher levels of tHcy, which is negatively correlated with GPx activity, low PON1 arylesterase activity and suboptimal levels of vitamin B(12).

  View details for DOI 10.1016/j.lfs.2005.09.040

  View details for Web of Science ID 000236718800012

  View details for PubMedID 16297937