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

Glorioso, Christin; Sabatini, Michael; Unger, Travis L.; Hashimoto, Takako; Monteggia, Lisa M.; Lewis, David A.; Mirnics, Károly

doi:10.1038/sj.mp.4001835

Cited by 94 publications

(89 citation statements)

References 104 publications

(127 reference statements)

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“…28 Instead, we employed the combination of magnitude of difference and statistical significance criteria in order to reduce false-positive findings and to eliminate statistically significant, but very small, expression changes likely to have a marginal biological effect. [28][29][30] When multiple probes met these criteria for a given transcript, the data from the probe detecting the largest |ALR| were reported and used for further analyses.…”

Section: Dna Microarraymentioning

confidence: 99%

“…For six of the GABA-related transcripts that met these microarray criteria for altered expression, real-time qPCR analyses 30 were performed on DLPFC samples from the same cohort of subjects. Using 50 ng of total RNA, cDNA synthesis by oligo dT primer and SuperScript II reverse transcriptase (Invitrogen) was conducted.…”

Section: Real-time Qpcrmentioning

confidence: 99%

“…Measurement was performed with two independent reverse transcriptions and four replicates for each reverse transcription. Mitochondrial ATP synthase F0 subunit 6 (ATP6) was used as a normalizing transcript 30 because all five probes for this transcript showed the most similar and consistent signal levels across all control and schizophrenia subjects in the microarray analysis ( Figure 1b). The dC T (C T for target transcripts -C T for ATP6), indicating the relative expression level of the target transcript to ATP6, was used for comparison by paired t-tests.…”

Section: Real-time Qpcrmentioning

confidence: 99%

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Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

et al. 2007

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In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in c-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex-and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD 67 ) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA A receptor subunits (a1, a4, b3, c2 and d). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD 67 , SST and a1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCKcontaining subpopulations of GABA neurons and in the signaling via certain GABA A receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.

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Section: Dna Microarraymentioning

confidence: 99%

Section: Real-time Qpcrmentioning

confidence: 99%

Section: Real-time Qpcrmentioning

confidence: 99%

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Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

et al. 2007

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“…36 Similar results were obtained using different threshold criteria for gene selection in the mouse data sets (in Figure 2: P < 0.001, changes greater than 20%). A similar approach was applied to assess correlations in transcriptome changes in CTX between Bdnf KO mice 37 and age-related profiles in Htr1b KO mice, as mouse probesets were directly comparable between the two studies.…”

Section: Mouse-human Age-effect Correlationmentioning

confidence: 99%

“…25 Here, we confirmed the previously reported downregulation of Bdnf transcripts with age in CTX 36,43,55 (WT: À1.63-fold change, P = 0.006; KO: À2.24-fold change, P = 0.002; Supplementary Tables S1 and S3) and showed that changes followed an 'early' pattern in Htr1b KO mice (Supplementary Table S1), thus suggesting a potential causative role for altered Bdnf function in the Htr1b KO age-related phenotype. Therefore, to investigate the potential contribution of Bdnf to the molecular phenotype of Htr1b KO mice, we took advantage of a recent report describing CTX gene expression changes occurring downstream from altered Bdnf function in Bdnf KO mice (embryonic or adult Bdnf KO , see 37 ) and investigated similarities between Bdnf-and age-induced transcriptome changes. In particular, if changes in Bdnf function participated in the age-related Htr1b KO molecular phenotype, then the effect of Bdnf KO on altered gene transcripts would correlate with the effect of aging, and should mostly follow an early pattern of changes in Htr1b KO mice.…”

Section: Mouse-human Phylogenetic Conservation Of Age-effect In Brainmentioning

confidence: 99%

Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity

Sibille

Leman

et al. 2007

Mol Psychiatry

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Normal aging of the brain differs from pathological conditions and is associated with increased risk for psychiatric and neurological disorders. In addition to its role in the etiology and treatment of mood disorders, altered serotonin (5-HT) signaling is considered a contributing factor to aging; however, no causative role has been identified in aging. We hypothesized that a deregulation of the 5-HT system would reveal its contribution to agerelated processes and investigated behavioral and molecular changes throughout adult life in mice lacking the regulatory presynaptic 5-HT 1B receptor (5-HT 1B R), a candidate gene for 5-HTmediated age-related functions. We show that the lack of 5-HT 1B R (Htr1b KO mice) induced an early age-related motor decline and resulted in decreased longevity. Analysis of life-long transcriptome changes revealed an early and global shift of the gene expression signature of aging in the brain of Htr1b KO mice. Moreover, molecular changes reached an apparent maximum effect at 18-months in Htr1b KO mice, corresponding to the onset of early death in that group. A comparative analysis with our previous characterization of aging in the human brain revealed a phylogenetic conservation of age-effect from mice to humans, and confirmed the early onset of molecular aging in Htr1b KO mice. Potential mechanisms appear independent of known central mechanisms (Bdnf, inflammation), but may include interactions with previously identified age-related systems (IGF-1, sirtuins). In summary, our findings suggest that the onset of age-related events can be influenced by altered 5-HT function, thus identifying 5-HT as a modulator of brain aging, and suggesting age-related consequences to chronic manipulation of 5-HT.

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

Cited by 94 publications

References 104 publications

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity

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

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