Reduced Dopamine Transporter Expression in the Amygdala of Subjects Diagnosed With Schizophrenia

Schizophrenia (SZ) is a chronic mental illness with behavioral abnormalities. Recent common variant based genome wide association studies and rare variant detection using next generation sequencing approaches have identified numerous variants that confer risk for SZ, but etiology remains unclear propelling continuing investigations. Using whole exome sequencing, we identified a rare heterozygous variant (c.545G > T; p.Cys182Phe) in Trace amine associated receptor 1 gene (TAAR1 6q23.2) in three affected members in a small SZ family. The variant predicted to be damaging by 15 prediction tools, causes breakage of a conserved disulfide bond in this G-protein-coupled receptor. On screening this intronless gene for additional variant(s) in ~800 sporadic SZ patients, we identified six rare protein altering variants (MAF < 0.001) namely p.Ser47Cys, p.Phe51Leu, p.Tyr294Ter, p.Leu295Ser in four unrelated north Indian cases (n = 475); p.Ala109Thr and p.Val250Ala in two independent Caucasian/African-American patients (n = 310). Five of these variants were also predicted to be damaging. Besides, a rare synonymous variant was observed in SZ patients. These rare variants were absent in north Indian healthy controls (n = 410) but significantly enriched in patients (p = 0.036). Conversely, three common coding SNPs (rs8192621, rs8192620 and rs8192619) and a promoter SNP (rs60266355) tested for association with SZ in the north Indian cohort were not significant (P > 0.05). TAAR1 is a modulator of monoaminergic pathways and interacts with AKT signaling pathways. Substantial animal model based pharmacological and functional data implying its relevance in SZ are also available. However, this is the first report suggestive of the likely contribution of rare variants in this gene to SZ.

Section: Discussionmentioning

confidence: 99%

Possible role of rare variants in Trace amine associated receptor 1 in schizophrenia

John

Kukshal

Bhatia

et al. 2017

“…Thus, these findings raise the possibility that decreased CSPG synthesis in glial cells may contribute PNN reductions in SZ. Speculatively, altered expression of transforming growth factor, and other growth factors known to powerfully regulate astroglial CSPG synthesis, may play a role in this mechanism (Benes et al, 2007; Markota et al, 2013; Smith and Strunz, 2005). In addition, recently reported genetic vulnerabilities for CSPG genes, including PTPRZ1 and neurocan (Buxbaum et al, 2008; Muhleisen et al, 2012; Ripke and Schizophrenia Working Group of the Psychiatric Genomics, 2014), may contribute to decrease CSPG synthesis in SZ.…”

Section: Potential Causes Of Pnn Abnormalitiesmentioning

confidence: 99%

Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia

Berretta

Pantazopoulos

Markota

et al. 2015

Self Cite

131

119

Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia. In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex. The formation of these specialized extracellular matrix (ECM) aggregates during postnatal development, their functions and association with distinct populations of GABAergic interneurons, bear great relevance to the pathophysiology of schizophrenia. PNNs gradually mature in an experience-dependent manner during late stages of postnatal development, overlapping with the prodromal period/age of onset of schizophrenia. Throughout adulthood, PNNs regulate neuronal properties, including synaptic remodeling, cell membrane compartmentalization and subsequent regulation of glutamate receptors and calcium channels, and susceptibility to oxidative stress. With the present paper, we discuss evidence for PNN abnormalities in schizophrenia, the potential functional impact of such abnormalities on inhibitory circuits and, in turn, cognitive and emotion processing. We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors. Notably, the composition of PNNs is regulated dynamically in response to factors such as fear, reward, stress, and immune response. This regulation occurs through families of matrix metalloproteinases that cleave ECM components, altering their functions and affecting plasticity. Several metalloproteinases have been proposed as vulnerability factors for schizophrenia. We speculate that the physiological process of PNN remodeling may be disrupted in schizophrenia as a result of interactions between matrix remodeling processes and immune system dysregulation. In turn, these mechanisms may contribute to dysfunction of GABAergic neurons.

“…In one such report, a highly significant positive correlation between 65 kDa glutamic acid decarboxylase (GAD65) immunoreactive terminals and doses of antipsychotics was observed in the hippocampus of subjects with schizophrenia, with neuroleptic-free patients showing the lowest numbers of terminals (Todtenkopf and Benes, 1998). In another more recent study testing the expression of the dopamine transporter in the amygdala, we detected robust decreases in subjects with schizophrenia (Markota et al, 2014). Numbers of putative terminals expressing dopamine transporter were significantly, and positively, correlated with lifetime exposure to antipsychotics, which pushed numbers to these terminals toward normal values.…”

Section: Pharmacological Therapymentioning

confidence: 60%

“…In addition, inclusion of a psychiatric control group with similar substance use characteristics represents a powerful study design for assessing specific outcome measures may be affected by drug exposure (e.g. Markota et al, 2014). Finally, chronic administration of specific drugs of abuse to experimental animals may be used, particularly if there are strong reasons to suspect that a key outcome variable may be affected.…”

Section: Substance Use Disordersmentioning

confidence: 99%

Searching human brain for mechanisms of psychiatric disorders. Implications for studies on schizophrenia

Berretta

Heckers

Beneš

2015

Self Cite

In the past 25 years, research on the human brain has been providing a clear path toward understanding the pathophysiology of psychiatric illnesses. The successes that have been accrued are matched by significant difficulties identifying and controlling a large number of potential confounding variables. By systematically and effectively accounting for unwanted variance in data from imaging and postmortem human brain studies, meaningful and reliable information regarding the pathophysiology of human brain disorders can be obtained. This perspective paper focuses on postmortem investigations to discuss some of the most challenging sources of variance, including diagnosis, comorbidity, substance abuse and pharmacological treatment, which confound investigations of human brain.