Relationship of Brain-Derived Neurotrophic Factor and Its Receptor TrkB to Altered Inhibitory Prefrontal Circuitry in Schizophrenia

Hashimoto, Takako; Bergen, Sarah E.; Nguyen, Quyen Le; Xu, Baoji; Monteggia, Lisa M.; Pierri, Joseph N.; Sun, Zhuoxin; Sampson, Allan R.; Lewis, David A.

doi:10.1523/jneurosci.4035-04.2005

Cited by 367 publications

(317 citation statements)

References 80 publications

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“…11,12 The observed expression changes also involved three independent probesets of cyclin D2 (CCND2), as well as genes that interact with CCND2 (cyclin-dependent kinase inhibitor 1C -CDKn1c and Ca/CaM-dependent protein kinase I gammaCAMK1g). Furthermore, the levels of the early immediate genes (IEG) activity regulated cytoskeletal-associated protein (ARC), early growth response 1 (EGR1), early growth response 2 (EGR2), FBJ osteosarcoma oncogene (FOS), dual specificity phosphatase 1 (DUSP1) and dual specificity phosphatase 6 (DUSP6) were also robustly altered, suggesting that BDNF levels are critical for regulation of a complex IEG-dependent transcription network.…”

Section: Resultsmentioning

confidence: 99%

“…11,12 To generate the animals for the current experimental series, two geneticallyaltered, independently-derived mouse strains were used. Reduction of BDNF expression was achieved using an inducible knockout (KO) of the BDNF gene where two transgenes, the tetracycline transactivator (tTA) gene driven by neuron-specific enolase (NSE) promoter (nse-tTA) 16 and the Cre recombinase gene under the control of tTA-responsive tetO promoter (tetO-cre) 17,18 regulate the deletion of floxed exon V of BNDF 19 in a tetracycline-dependent manner.…”

Section: Methodsmentioning

confidence: 99%

“…Maximum recombination was achieved 4 weeks after doxycycline removal 11 resulting in a > 70% reduction in BDNF transcript and protein levels. 11,12 Littermates with NSE-tTA and tetO-cre transgenes were used as controls. These mice expressed similar levels of BDNF as wild type mice.…”

Section: Methodsmentioning

confidence: 99%

“…Our previously published study suggested that the PARV containing interneuronal class is not affected in either one of these BDNF-ablated mice and that the overall GABA-ergic phenotype of the interneurons, judged by presence of GAD1 transcript levels, is preserved. 12 However, both the microarray and qPCR data sets strongly suggested that BDNF expression has a critical effect on SST, NPY and TAC1-containing interneuronal populations. In addition, in situ hybridization ( Figure 5) revealed a robust and significant downregulation of SST in the neocortex of both the adult and embryonic BDNF-ablated mice (1.7 and 1.9-fold, respectively) in another cohort of mice.…”

Section: Validation Of Microarray Findingsmentioning

confidence: 99%

“…For example, the inducible deletion of BDNF 11 does not result in altered mRNA levels of the 67 kDa isoform of glutamic acid decarboxylase (GAD1) or parvalbumin (PARV) in adult mice. 12 Furthermore, the dependence of any given neuronal type on BDNF may differ as a function of developmental stage. 13 For example, BDNF is a critical mediator of the maturation of glutamatergic synapses in developing mouse somatosensory cortex.…”

Section: Introductionmentioning

confidence: 99%

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Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

et al. 2006

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Validation Of Microarray Findingsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

et al. 2006

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Reduced Cortical Cannabinoid 1 Receptor Messenger RNA and Protein Expression in Schizophrenia

Eggan

Hashimoto²,

Lewis³

2008

Arch Gen Psychiatry

204

197

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Context Cannabis use is associated with both impaired cognitive functions, including working memory, and an increased risk of schizophrenia. Schizophrenia is characterized by impairments in working memory that are associated with reduced γ-aminobutyric acid (GABA) neurotransmission in the dorsolateral prefrontal cortex. The cannabinoid 1 receptor (CB1R) is highly expressed in the dorsolateral prefrontal cortex, is contained in the axon terminals of a subpopulation of perisomatic-targeting GABA neurons, and, when activated, suppresses the release of GABA. Objective To determine the potential relationship between CB1R signaling and altered GABA neurotransmission in schizophrenia by evaluating CB1R messenger RNA (mRNA) and protein expression in the dorsolateral pre-frontal cortex. Design In situ hybridization and immunocytochemistry techniques were used to examine the cortical levels of CB1R mRNA and protein, respectively. Setting Brain specimens were obtained from autopsies conducted at the Allegheny County Medical Examiner’s Office, Pittsburgh, Pennsylvania. Participants Postmortem brain specimens from 23 pairs of subjects with schizophrenia and age-, sex-, and postmortem interval–matched comparison subjects, as well as brain specimens from 18 macaque monkeys with long-term exposure to haloperidol, olanzapine, or placebo. Main Outcome Measures Optical density measures of CB1R mRNA expression and protein levels and correlations with previously reported glutamic acid decarboxylase 67 and cholecystokinin mRNA measures. Results Levels of CB1R mRNA were significantly lower by 14.8% in the subjects with schizophrenia. Similarly, CB1R protein levels, assessed by radioimmunocytochemistry and standard immunocytochemistry, were significantly decreased by 11.6% and 13.9%, respectively. Group differences in CB1R mRNA levels were significantly correlated with those in glutamic acid decarboxylase 67 and cholecystokinin mRNA levels. Expression of CB1R mRNA was not changed in antipsychotic-exposed monkeys, and neither CB1R mRNA levels nor protein levels were affected by potential confounding factors in the subjects with schizophrenia. Conclusions This combination of findings suggests the testable hypothesis that reduced CB1R mRNA and protein levels in schizophrenia represent a compensatory mechanism to increase GABA transmission from perisomatic-targeting cholecystokinin interneurons with impaired GABA synthesis.

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Diagnostic Specificity and Association With Cognition of Molecular Alterations in Prefrontal Somatostatin Neurons in Schizophrenia

Dienel,

Dowling,

Barile

et al. 2023

JAMA Psychiatry

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ImportanceIndividuals with schizophrenia (SZ) exhibit pronounced deficits in somatostatin (SST) messenger RNA (mRNA) levels in the dorsolateral prefrontal cortex (DLPFC). Molecularly distinct subtypes of SST neurons, located in the superficial and deep zones of the DLPFC, are thought to contribute to different functional processes of this region; understanding the specificity of SST alterations in SZ across these zones could inform the functional consequences of those alterations, including cognitive impairments characteristic of SZ.ObjectiveTo quantify mRNA levels of SST and related neuropeptides in the DLPFC in individuals with SZ, bipolar disorder (BPD), or major depressive disorder (MDD) and unaffected comparison individuals.Design, Setting, and ParticipantsThis case-control study, conducted from January 20, 2020, to March 30, 2022, used postmortem brain tissue specimens previously obtained from individuals with SZ, MDD, or BPD and unaffected individuals from a community population through 2 medical examiners’ offices. Demographic, clinical, and educational information was ascertained through psychological autopsies.ExposuresDiagnosis of SZ, BPD, or MDD.Main Outcome and MeasuresThe main outcome was levels of SST and related neuropeptide mRNA in 2 DLPFC zones, examined using laser microdissection and quantitative polymerase chain reaction or fluorescent in situ hybridization (FISH). Findings were compared using educational attainment as a proxy measure of premorbid cognition.ResultsA total of 200 postmortem brain specimens were studied, including 65 from unaffected comparison individuals (42 [65%] male; mean [SD] age, 49.2 [14.1] years); 54 from individuals with SZ (37 [69%] male; mean [SD] age, 47.5 [13.3] years); 42 from individuals with MDD (24 [57%] male; mean [SD] age, 45.6 [12.1] years); and 39 from individuals with BPD (23 [59%] male; mean (SD) age, 46.2 [12.5] years). Compared with unaffected individuals, levels of SST mRNA were lower in both superficial (Cohen d, 0.68; 95% CI, 0.23-1.13; P = .004) and deep (Cohen d, 0.60; 95% CI, 0.16-1.04; P = .02) DLPFC zones in individuals with SZ; findings were confirmed using FISH. Levels of SST were lower only in the superficial zone in the group with MDD (Cohen d, 0.58; 95% CI, 0.14-1.02; P = .12), but the difference was not significant; SST levels were not lower in either zone in the BPD group. Levels of neuropeptide Y and tachykinin 1 showed similar patterns. Neuropeptide alterations in the superficial, but not deep, zone were associated with lower educational attainment only in the group with SZ (superficial: adjusted odds ratio, 1.71 [95% CI, 1.11-2.69]; P = .02; deep: adjusted odds ratio, 1.08 [95% CI, 0.64-1.84]; P = .77).Conclusions and RelevanceThe findings revealed diagnosis-specific patterns of molecular alterations in SST neurons in the DLPFC, suggesting that distinct disease processes are reflected in the differential vulnerability of SST neurons in individuals with SZ, MDD, and BPD. In SZ, alterations specifically in the superficial zone may be associated with cognitive dysfunction.

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Relationship of Brain-Derived Neurotrophic Factor and Its Receptor TrkB to Altered Inhibitory Prefrontal Circuitry in Schizophrenia

Cited by 367 publications

References 80 publications

Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

Reduced Cortical Cannabinoid 1 Receptor Messenger RNA and Protein Expression in Schizophrenia

Diagnostic Specificity and Association With Cognition of Molecular Alterations in Prefrontal Somatostatin Neurons in Schizophrenia

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