Increased Opioid Dependence in a Mouse Model of Panic Disorder

Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients

Dissociation between CA3-CA1 synaptic plasticity and associative learning in TgNTRK3 transgenic mice

Neurotrophins and their cognate receptors might serve as feedback regulators for the efficacy of synaptic transmission.Weanalyzed miceoverexpressing TrkC (TgNTRK3) for synaptic plasticity and the expression of glutamate receptor subunits. Animals were conditionedusing a trace [conditioned stimulus (CS), tone; unconditioned stimulus (US), shock] paradigm. A single electrical pulse presented to theSchaffer collateral– commissural pathway during the CS–US interval evoked a monosynaptic field EPSP (fEPSP) at ipsilateral CA1pyramidal cells. In wild types, fEPSP slopes increased across conditioning sessions and decreased during extinction, being linearlyrelated to learning evolution. In contrast, fEPSPs in TgNTRK3 animals reached extremely high values, not accompanied with a proportionateincrease in their learning curves. Long-term potentiation evoked in conscious TgNTRK3 was also significantly longer lasting thanin wild-type mice. These functional alterations were accompanied by significant changes inNR1andNR2BNMDAreceptor subunits, withno modification of NR1Ser 896 or NR1Ser 897 phosphorylation. No changes of AMPA and kainate subunits were detected. Results indicatethat the NT-3/TrkC cascade could regulate synaptic transmission and plasticity through modulation of glutamatergic transmission at theCA3–CA1 synapse

Systematic Collaborative Reanalysis of Genomic Data Improves Diagnostic Yield in Neurologic Rare Diseases

Altres ajuts: Generalitat de Catalunya, Departament de Salut; Generalitat de Catalunya, Departament d'Empresa i Coneixement i CERCA Program; Ministerio de Ciencia e Innovación; Instituto Nacional de Bioinformática; ELIXIR Implementation Studies (CNAG-CRG); Centro de Investigaciones Biomédicas en Red de Enfermedades Raras; Centro de Excelencia Severo Ochoa; European Regional Development Fund (FEDER).Many patients experiencing a rare disease remain undiagnosed even after genomic testing. Reanalysis of existing genomic data has shown to increase diagnostic yield, although there are few systematic and comprehensive reanalysis efforts that enable collaborative interpretation and future reinterpretation. The Undiagnosed Rare Disease Program of Catalonia project collated previously inconclusive good quality genomic data (panels, exomes, and genomes) and standardized phenotypic profiles from 323 families (543 individuals) with a neurologic rare disease. The data were reanalyzed systematically to identify relatedness, runs of homozygosity, consanguinity, single-nucleotide variants, insertions and deletions, and copy number variants. Data were shared and collaboratively interpreted within the consortium through a customized Genome-Phenome Analysis Platform, which also enables future data reinterpretation. Reanalysis of existing genomic data provided a diagnosis for 20.7% of the patients, including 1.8% diagnosed after the generation of additional genomic data to identify a second pathogenic heterozygous variant. Diagnostic rate was significantly higher for family-based exome/genome reanalysis compared with singleton panels. Most new diagnoses were attributable to recent gene-disease associations (50.8%), additional or improved bioinformatic analysis (19.7%), and standardized phenotyping data integrated within the Undiagnosed Rare Disease Program of Catalonia Genome-Phenome Analysis Platform functionalities (18%)

ELISA versus PCR for diagnosis of chronic Chagas disease: systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Most current guidelines recommend two serological tests to diagnose chronic Chagas disease. When serological tests are persistently inconclusive, some guidelines recommend molecular tests. The aim of this investigation was to review chronic Chagas disease diagnosis literature and to summarize results of ELISA and PCR performance.</p> <p>Methods</p> <p>A systematic review was conducted searching remote databases (MEDLINE, LILACS, EMBASE, SCOPUS and ISIWeb) and full texts bibliography for relevant abstracts. In addition, manufacturers of commercial tests were contacted. Original investigations were eligible if they estimated sensitivity and specificity, or reliability -or if their calculation was possible - of ELISA or PCR tests, for chronic Chagas disease.</p> <p>Results</p> <p>Heterogeneity was high within each test (ELISA and PCR) and threshold effect was detected only in a particular subgroup. Reference standard blinding partially explained heterogeneity in ELISA studies, and pooled sensitivity and specificity were 97.7% [96.7%-98.5%] and 96.3% [94.6%-97.6%] respectively. Commercial ELISA with recombinant antigens studied in phase three investigations partially explained heterogeneity, and pooled sensitivity and specificity were 99.3% [97.9%-99.9%] and 97.5% [88.5%-99.5%] respectively. ELISA's reliability was seldom studied but was considered acceptable. PCR heterogeneity was not explained, but a threshold effect was detected in three groups created by using guanidine and boiling the sample before DNA extraction. PCR sensitivity is likely to be between 50% and 90%, while its specificity is close to 100%. PCR reliability was never studied.</p> <p>Conclusions</p> <p>Both conventional and recombinant based ELISA give useful information, however there are commercial tests without technical reports and therefore were not included in this review. Physicians need to have access to technical reports to understand if these serological tests are similar to those included in this review and therefore correctly order and interpret test results. Currently, PCR should not be used in clinical practice for chronic Chagas disease diagnosis and there is no PCR test commercially available for this purpose. Tests limitations and directions for future research are discussed.</p

Role of NTRK3 in the extinction of fear memories and streess-coping: studies in a mouse model of panic disorder

The correct development and function of CNS is critical for brain health of the organism. Early or chronic stress causes prominent alterations in brain function, and affects the expression of neurotrophic factors in limbic brain regions involved in the regulation of mood and cognition. Recent evidences have opened the idea that in complex organisms, an altered expression of certain neurotrophins by stress could be involved in the onset and pathophysiology of most psychiatric disorders, such as depression, squizophrenia or anxiety disorders. It is hypothesized that altered levels of neurotrophic factors could contribute to the atrophy and cell death of these regions, including the hippocampus and prefrontal cortex, which would produce a malfunction in limbic-related areas, and as a consequence, a precipitation or worsening of psychiatric illnesses. We were interested in panic disorder pathophysiology, which is a stress-related disorder and is characterized by an altered cognitive processing of emotional information. Although little evidence has been found supporting a neurotrophic role in PD, recent data has revealed that NT-3/TrkC signaling might play a key role in limbic system morphology and function. Therefore, we suggest that NT-3/TrkC system is involved in PD pathogenesis. The main objective in the work of this doctoral thesis lie to determine the role of NTRK3 gene, that codifies for TrKC, in emotional cognition and stress response processes that underlies PD. To this end, we used a genetically modified mouse model of NTRK3 overexpression, which was validated as a model of PD. Here, it is characterized the effects produced by the increase of NTRK3 expression in the CNS, focusing in neural alterations that might influence changes in cognitive processes involved in coping strategies. Moreover, it is studied the mechanisms that underlie in these processes by different approaches, 1/physiologically, measuring the HPA axis response, 2/brain activation, analyzing the activation pattern to a stress stimulus, 3/cellular and gene expression profiling, characterizing key brain regions in cognitive processes, and 4/pharmacologically, studying neurotransmitters function

Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a/npanic disorder mouse model

Panic attacks are a hallmark in panic disorder (PAND). During the panic attack, a strong association with the surrounding context is established suggesting that the hippocampus may be critically involved in the pathophysiology of PAND, given its role in contextual processing. We previously showed that variation in the expression of the neurotrophin tyrosine kinase receptor type 3 (NTRK3) in both PAND patients and a transgenic mouse model (TgNTRK3) may have a role in PAND pathophysiology. Our study examines hippocampal function and activation of the brain fear network in TgNTRK3 mice. TgNTRK3 mice showed increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Moreover, TgNTRK3 mice also showed an unbalanced excitation-to-inhibition ratio in the hippocampal cornu ammonis 3 (CA3)-CA1 subcircuit toward hyperexcitability. The resulting hippocampal hyperexcitability underlies the enhanced fear memories, as supported by the efficacy of tiagabine, a GABA reuptake inhibitor, to rescue fear response. The fearful phenotype appears to be the result of hippocampal hyperexcitability and aberrant fear circuit activation. We conclude that NTRK3 plays a role in PAND by regulating hippocampus-dependent fear memories.The laboratory of M.D. is supported by Departament d'Universitats, Recerca i Societat de la Informació (Grups consolidats 09 2009SGR1313). This work was supported by Grants SAF2010-16427, SAF2007-31093-E, and FIS (PI 082038); Marató TV3; the Jerome Lejeune, Koplowitz, and Areces Foundations; and the European Union (LSHG-CT-2006-037627; CureFXS ERare-EU/FIS PS09102673). The Centro de Investigación Biomédica en Red de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III. M.S. was supported by Fundação para a Ciência e Tecnologica (Portugal) with a postdoctoral fellowship, and D.D. was supported by a La Caixa International PhD Programme fellowshi

Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a/npanic disorder mouse model

Panic attacks are a hallmark in panic disorder (PAND). During the panic attack, a strong association with the surrounding context is established suggesting that the hippocampus may be critically involved in the pathophysiology of PAND, given its role in contextual processing. We previously showed that variation in the expression of the neurotrophin tyrosine kinase receptor type 3 (NTRK3) in both PAND patients and a transgenic mouse model (TgNTRK3) may have a role in PAND pathophysiology. Our study examines hippocampal function and activation of the brain fear network in TgNTRK3 mice. TgNTRK3 mice showed increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Moreover, TgNTRK3 mice also showed an unbalanced excitation-to-inhibition ratio in the hippocampal cornu ammonis 3 (CA3)-CA1 subcircuit toward hyperexcitability. The resulting hippocampal hyperexcitability underlies the enhanced fear memories, as supported by the efficacy of tiagabine, a GABA reuptake inhibitor, to rescue fear response. The fearful phenotype appears to be the result of hippocampal hyperexcitability and aberrant fear circuit activation. We conclude that NTRK3 plays a role in PAND by regulating hippocampus-dependent fear memories.The laboratory of M.D. is supported by Departament d'Universitats, Recerca i Societat de la Informació (Grups consolidats 09 2009SGR1313). This work was supported by Grants SAF2010-16427, SAF2007-31093-E, and FIS (PI 082038); Marató TV3; the Jerome Lejeune, Koplowitz, and Areces Foundations; and the European Union (LSHG-CT-2006-037627; CureFXS ERare-EU/FIS PS09102673). The Centro de Investigación Biomédica en Red de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III. M.S. was supported by Fundação para a Ciência e Tecnologica (Portugal) with a postdoctoral fellowship, and D.D. was supported by a La Caixa International PhD Programme fellowshi

Increased opioid dependence in a mouse model of panic disorder

Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.This work was funded by the Spanish Ministry of Education and Sciences SAF2007-31093-E, SAF2007-60827, and SAF2008-03612, 2009SGR1313 and Health (PI082038), Fundación Areces, Marató TV3, Phecomp (EU LSHM-CT-2007-037669; 037627-AnEUploidy), Ministerio de Salud y Consumo (RTA G03/005 and PI05/0513, PI082038), University of the Basque Country (1/UPV 0026.327-E-15924/2004 and GIU07/46), Plan Nacional sobre Drogas (PNDMSC 2005) and CIBERER. Patricia Murtra is a scientific researcher supported by the Juan de la Cierva program of Ministerio de Ciencia y Tecnología. Teresa Zamalloa was supported by a predoctoral fellowship from the Basque Governmen

Increased opioid dependence in a mouse model of panic disorder

Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients