Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes

Zarchi, Omer; Carmel, Miri; Avni, Chen; Attias, Josef; Frisch, Amos; Michaelovsky, Elena; Patya, Miriam; Green, Tamar; Weinberger, Ronnie; Weizman, Abraham; Gothelf, Doron

doi:10.1016/j.jpsychires.2013.07.004

Cited by 36 publications

(33 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Elevation of L-proline levels in 22q11.2 deletion carriers is as an important component of the psychiatric risk associated with this genomic lesion and depends on the presence of hypomorphic PRODH alleles in the retained copy on the intact chromosome (Raux et al, 2007; Bender et al, 2005; Chakravarti, 2002; Liu et al, 2002; Willis et al, 2008; Zarchi et al, 2013). Significantly, the severity of hyperprolinemia in these patients correlates with risk of psychosis (Raux et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade

et al. 2016

View full text Add to dashboard Cite

SUMMARY Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically-relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade

et al. 2016

View full text Add to dashboard Cite

show abstract

“…For example, if everything is surprising, then it would be difficult to elicit oddball, violation or omission responses – as measured electrophysiologically. This explains impoverished mismatch negativity responses in schizophrenia (Dima et al, 2012, Umbricht and Krljes, 2005, Zarchi et al, 2013). Furthermore, it explains the peculiar resistance to illusions that is characteristic of schizophrenia (Barch et al, 2012, Brown et al, 2013, Butler et al, 2008, Jardri and Deneve, 2013).…”

Section: Gain Control and Precision In Schizophreniamentioning

confidence: 97%

The dysconnection hypothesis (2016)

Friston

Brown

Siemerkus

et al. 2016

Schizophrenia Research

487

361

View full text Add to dashboard Cite

Twenty years have passed since the dysconnection hypothesis was first proposed (Friston and Frith, 1995; Weinberger, 1993). In that time, neuroscience has witnessed tremendous advances: we now live in a world of non-invasive neuroanatomy, computational neuroimaging and the Bayesian brain. The genomics era has come and gone. Connectomics and large-scale neuroinformatics initiatives are emerging everywhere. So where is the dysconnection hypothesis now? This article considers how the notion of schizophrenia as a dysconnection syndrome has developed – and how it has been enriched by recent advances in clinical neuroscience. In particular, we examine the dysconnection hypothesis in the context of (i) theoretical neurobiology and computational psychiatry; (ii) the empirical insights afforded by neuroimaging and associated connectomics – and (iii) how bottom-up (molecular biology and genetics) and top-down (systems biology) perspectives are converging on the mechanisms and nature of dysconnections in schizophrenia.

show abstract

“…Additionally, unmasking of other sequence variants throughout the genome and/or in the non-deleted allele that may affect the activities of the gene products has also been hypothesized to contribute to the variability of features for 22q11.2 deletions [Brzustowicz and Bassett, 2012;Zarchi et al, 2013;Carmel et al, 2014;Gothelf et al, 2014;Radoeva et al, 2014]. Other studies have suggested a possible gender effect in proximal deletion subjects, owing to the interaction of estrogen with COMT , but additional studies are needed to clarify whether there is indeed a relationship in DGS patients [Coman et al, 2010;Yu et al, 2012].…”

Section: Variability Of Phenotypementioning

confidence: 99%

22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features

Burnside

2015

Cytogenet Genome Res

1,441

149

View full text Add to dashboard Cite

Chromosome 22q11.21 contains a cluster of low-copy repeats (LCRs), referred to as LCR22A-H, that mediate meiotic non-allelic homologous recombination, resulting in either deletion or duplication of various intervals in the region. The deletion of the DiGeorge/velocardiofacial syndrome interval LCR22A-D is the most common recurrent microdeletion in humans, with an estimated incidence of ∼1:4,000 births. Deletion of other intervals in 22q11.21 have also been described, but the literature is often confusing, as the terms ‘proximal', ‘nested', ‘distal', and ‘atypical' have all been used to describe various of the other intervals. Individuals with deletions tend to have features with widely variable expressivity, even among families. This review concisely delineates each interval and classifies the reported literature accordingly.

show abstract

Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes

Cited by 36 publications

References 40 publications

Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade

Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade

The dysconnection hypothesis (2016)

22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features

Contact Info

Product

Resources

About