scholarly journals Reductions in midbrain GABAergic and dopamine neuron markers are linked in schizophrenia

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Tertia D. Purves-Tyson ◽  
Amelia M. Brown ◽  
Christin Weissleder ◽  
Debora A. Rothmond ◽  
Cynthia Shannon Weickert
Keyword(s):  
Tyrosine Hydroxylase ◽  
Statistical Significance ◽  
Inhibitory Neuron ◽  
Brain Regions ◽  
Neurotransmitter System ◽  
Molecular Changes ◽  
Alpha Subunits ◽  
Inhibitory Neurotransmission ◽  
Inflammatory Status ◽  
Gad 65

AbstractReductions in the GABAergic neurotransmitter system exist across multiple brain regions in schizophrenia and encompass both pre- and postsynaptic components. While reduced midbrain GABAergic inhibitory neurotransmission may contribute to the hyperdopaminergia thought to underpin psychosis in schizophrenia, molecular changes consistent with this have not been reported. We hypothesised that reduced GABA-related molecular markers would be found in the midbrain of people with schizophrenia and that these would correlate with dopaminergic molecular changes. We hypothesised that downregulation of inhibitory neuron markers would be exacerbated in schizophrenia cases with high levels of neuroinflammation. Eight GABAergic-related transcripts were measured with quantitative PCR, and glutamate decarboxylase (GAD) 65/67 and GABAA alpha 3 (α3) (GABRA3) protein were measured with immunoblotting, in post-mortem midbrain (28/28 and 28/26 control/schizophrenia cases for mRNA and protein, respectively), and analysed by both diagnosis and inflammatory subgroups (as previously defined by higher levels of four pro-inflammatory cytokine transcripts). We found reductions (21 – 44%) in mRNA encoding both presynaptic and postsynaptic proteins, vesicular GABA transporter (VGAT), GAD1, and parvalbumin (PV) mRNAs and four alpha subunits (α1, α2, α3, α5) of the GABAA receptor in people with schizophrenia compared to controls (p < 0.05). Gene expression of somatostatin (SST) was unchanged (p = 0.485). We confirmed the reduction in GAD at the protein level (34%, p < 0.05). When stratifying by inflammation, only GABRA3 mRNA exhibited more pronounced changes in high compared to low inflammatory subgroups in schizophrenia. GABRA3 protein was expressed by 98% of tyrosine hydroxylase-positive neurons and was 23% lower in schizophrenia, though this did not reach statistical significance (p > 0.05). Expression of transcripts for GABAA receptor alpha subunits 2 and 3 (GABRA2, GABRA3) were positively correlated with tyrosine hydroxylase (TH) and dopamine transporter (DAT) transcripts in schizophrenia cases (GABRA2; r > 0.630, GABRA3; r > 0.762, all p < 0.001) but not controls (GABRA2; r < − 0.200, GABRA3; r < 0.310, all p > 0.05). Taken together, our results support a profound disruption to inhibitory neurotransmission in the substantia nigra regardless of inflammatory status, which provides a potential mechanism for disinhibition of nigrostriatal dopamine neurotransmission.

scholarly journals Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

2021 ◽  
Vol 6 (2) ◽  
pp. 48
Author(s):  
Elisa Innocenzi ◽  
Ida Cariati ◽  
Emanuela De Domenico ◽  
Erika Tiberi ◽  
Giovanna D’Arcangelo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Aerobic Exercise ◽  
Frontal Cortex ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Brain Regions ◽  
Synaptic Function ◽  
Molecular Changes ◽  
Beneficial Effects ◽  
The Impact

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

scholarly journals INVOLVEMENT OF CATECHOLAMINES IN THE MYOCARDIUM OF RATS SUBMITTED TO EXPERIMENTAL MODEL OF PORTAL HYPERTENSION

2018 ◽  
Vol 31 (3) ◽  
Author(s):  
Antonella VINHOLI ◽  
Marília Da Cruz FAGUNDES ◽  
Danieli Cristina PIGOZZO ◽  
Fernando Bermudez KUBRUSLY ◽  
Luiz Fernando KUBRUSLY ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Tyrosine Hydroxylase ◽  
Portal Vein ◽  
Mesenteric Artery ◽  
Wistar Rats ◽  
Statistical Significance ◽  
Immunohistochemical Analysis ◽  
Immunohistochemical Expression ◽  
Marked Area

ABSTRACT Background: The role of autonomic nervous system in the development and maintenance of portal hypertension is not fully elucidated. It is known that the gene expression of norepinephrine in the superior mesenteric artery varies with time, and it may contribute for splanchnic vasodilation and its consequent hemodynamic repercussions. It is still not known exactly how the adrenergic expression behaves at the heart level in the initial stages of this process. Aim: To evaluate the immunohistochemical expression of the enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), involved in the synthesis of norepinephrine, in the myocardium of rats submitted to partial ligation of the portal vein. Methods: Twenty-four Wistar rats were divided into two groups: Sham Operated and Portal Hypertension. The partial ligation was performed in the Portal Hypertension group, and after 1/6/24 h and 3/5/14 days the animals were euthanized. Immunohistochemical analysis was performed to quantify the expression of the stained enzyme using the ImageJ program. Results: The Portal Hypertension group expressed percentages between 4.6-6% of the marked area, while the Sham Operated group varied between 4-5%. Although there was no statistical significance, the percentage stained in the Portal Hypertension group followed an increasing pattern in the first 6 h and a decreasing pattern after 24 h, which was not observed in the Sham Operated group. Conclusion: The expression of noradrenaline in rat myocardium during the first two weeks after partial ligation of the portal vein, with tyrosine hydroxylase as marker, did not show differences between groups over time.

scholarly journals Tyrosine Hydroxylase Phosphorylation in Catecholaminergic Brain Regions: A Marker of Activation following Acute Hypotension and Glucoprivation

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e50535 ◽  
Author(s):  
Hanafi A. Damanhuri ◽  
Peter G. R. Burke ◽  
Lin K. Ong ◽  
Larisa Bobrovskaya ◽  
Phillip W. Dickson ◽  
...  
Keyword(s):  
Tyrosine Hydroxylase ◽  
Brain Regions ◽  
Acute Hypotension ◽  
Tyrosine Hydroxylase Phosphorylation

Coexistence of GAD-65 and GAD-67 with tyrosine hydroxylase and nitric oxide synthase in amacrine and interplexiform cells of the primate, Cebus apella

2003 ◽  
Vol 20 (2) ◽  
pp. 153-163 ◽  
Author(s):  
BELMIRA LARA DA SILVEIRA ANDRADE DA COSTA ◽  
JAN NORA HOKOÇ
Keyword(s):  
Nitric Oxide ◽  
Tyrosine Hydroxylase ◽  
Nitric Oxide Synthase ◽  
World Monkey ◽  
Amacrine Cells ◽  
Cebus Apella ◽  
Retinal Cell ◽  
Inner Plexiform Layer ◽  
Gad 65 ◽  
Oxide Synthase

The expression of glutamate decarboxylase forms, GAD-65 and GAD-67, in GABAergic cells was studied by immunocytochemistry in the retina of the New World monkey, Cebus apella. In the innermost rows of the inner nuclear layer (INL), somata that express GABA correspond to about 45% of the total number of cells in the central retina and about 25% on the periphery. Three subsets of GABAergic amacrine cells were identified along the horizontal meridian: about 5% express only GAD-65 and 40% GAD-67, and approximately 50% contain both forms of GAD. In the INL, GAD-65 immunoreactivity was detected in broad bands around strata 1, 3, and 5. GAD-67 immunoreactivity was observed throughout all strata. Somata that expressed GAD-67 exclusively stratified only in narrow bands around strata 2 and 4 of the INL and colocalized with β2 and β3 subunits of GABA-A receptor. Interplexiform and amacrine cells that express GABA also express tyrosine hydroxylase (TH) or nitric oxide synthase (NOS). GAD-67 colocalized with TH or NOS in presumed amacrine cells of the inner plexiform layer (IPL) and ganglion cell layer (GCL). GAD-65 was expressed in the TH- and NOS-immunoreactive interplexiform and amacrine cells, respectively. Different from what has been described in other mammals, TH and NOS were coexpressed in some neurons, indicating a partial overlap in retinal cell populations containing dopamine or nitric oxide in this primate.

scholarly journals microRNA profiling uncovers region-specific molecular correlates of threat responses in a marmoset model of anxiety

2021 ◽  
Author(s):  
Natalia Popa ◽  
Angela C Roberts ◽  
Andrea M Santangelo ◽  
Eduardo Gascon
Keyword(s):  
Emotional Regulation ◽  
Brain Regions ◽  
Molecular Heterogeneity ◽  
Depression And Anxiety ◽  
Behavioral Differences ◽  
Brain Areas ◽  
Molecular Changes ◽  
Highly Correlated ◽  
Cortical Regions ◽  
And Behavior

Background: Neuroimaging studies have consistently reported that stress-related disorders such as depression and anxiety impinge on the activity of emotion regulation networks, namely in the ventromedial prefrontal cortex (vmPFC). This circuitry is known to be extensively modulated by serotonin and it has been long shown that genetic polymorphisms in the serotonin transporter gene (SLC6A4) are linked to anxiey and depression. vmPFC encompasses different brain regions in terms of cytoarchitecture, activity and connectivity. However, molecular heterogeneity within the vmPFC and how these differences affect emotional regulation and behavior have not been elucidated. Methods: Here, we took advantage of recently described polymorphisms in marmoset SLC6A4 gene linked to alter threat responses. Using FACS-sorted cells from different brain areas of genotyped marmosets, we tested the hypothesis that specific molecular changes in precise regions of the vmPFC underlie the behavioral differences and can be associated with high anxiety-like trait. Results: miRNA analysis of FACS-sorted cells from marmoset cortex revealed that clear miRNA profiles can be identified for different cell subsets (NeuN+ versus NeuN- cells) or cortical regions (visual cortex versus vmPFC). More importantly, marmosets bearing different SLC6A4 polymorphisms show distinct miRNAs signatures specifically in vmPFC area 32 neurons but not in the closely related vmPFC area 25 neurons. Finally, levels of these miRNAs were highly correlated to the anxiety-like score in a test of uncertain threat. Conclusions: These data demonstrate that molecular changes within area 32 likely underlie the differential anxiety-like responses associated with SLC6A4 polymorphisms.

Effects of thiopental anesthesia on local rates of cerebral protein synthesis in rats

1998 ◽  
Vol 274 (5) ◽  
pp. E852-E859
Author(s):  
C. Beebe Smith ◽  
C. Eintrei ◽  
J. Kang ◽  
Y. Sun
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Statistical Significance ◽  
Brain Regions ◽  
Male Rats ◽  
Protein Breakdown ◽  
Relative Contribution ◽  
Anesthetized Rats ◽  
Cerebral Protein Synthesis ◽  
The Brain

We have examined the effects of a surgical level of thiopental anesthesia in adult male rats on local rates of cerebral protein synthesis with the quantitative autoradiographicl-[1-14C]leucine method. The relative contribution of leucine derived from protein breakdown to the intracellular precursor amino acid pool for protein synthesis was found to be statistically significantly decreased in the anesthetized rats compared with controls. In the brain as a whole and in 30 of the 35 brain regions examined, rates of protein synthesis were decreased (1–11%) in the anesthetized rats. Decreases were statistically significant ( P ≤ 0.05) in the brain as a whole and in six of the regions, and they approached statistical significance in an additional 13 regions, indicating a tendency for a generalized but small effect.

scholarly journals Comparison of PET [15O]Water Studies with 6-Minute and 10-Minute InterScan Intervals: Single-Subject and Group Analyses

1999 ◽  
Vol 19 (5) ◽  
pp. 570-582 ◽  
Author(s):  
Jolanta Chmielowska ◽  
Robert C. Coghill ◽  
Richard E. Carson ◽  
Kenji Ishii ◽  
Robert Chen ◽  
...  
Keyword(s):  
Statistical Power ◽  
Statistical Significance ◽  
Group Analysis ◽  
Statistical Parametric Mapping ◽  
Brain Regions ◽  
Single Subject ◽  
Local Variance ◽  
Study Duration ◽  
Minute Interval ◽  
Variance Estimate

The authors recently showed that [15O]water PET data obtained with a short interscan interval (6 minutes) produced similar results whether or not the residual background from the previous scan is subtracted. The purpose of the present study was to compare scans obtained during motor activation using a short (6-minute) interscan interval protocol with those obtained with a standard (10-minute) protocol in the same scanning session. Single-subject and group analyses were performed using Worsley's method, which uses a pooled variance estimate and statistical parametric mapping with a local variance estimate. High consistency in both the activation maps, i.e., the number of activated motor brain structures and the Talairach coordinates of peak intensities of the activated regions, was obtained in the 6- and 10-minute studies in both single-subject and group analyses. However, in comparison to the 6-minute studies, a larger cluster size of activated brain regions and an approximately 20% higher peak activation in these regions were observed in the 10-minute studies with the same number of replicates. Analysis of these results suggests that using a 6-minute interval with an increased number of replications, i.e., without changing the subject's total study duration, should produce comparable statistical power to that of the 10-minute interval for group analysis and increased statistical power for single-subject analyses that use a local variance estimate because of increased degrees of freedom. Alternatively, with a small increase in the number of scans and the use of a 6-minute interscan interval, a comparable level of statistical significance may be achieved for single-subject experiments that use a local variance estimate, with an overall shortening of the study duration.

Sign in / Sign up

Export Citation Format

Share Document