Independent evidence for the selective influence of GABAA receptors on one component of the bipolar disorder phenotype

Breuer, René; Hamshere, Marian L.; Strohmaier, Jana; Mattheisen, Manuel; Degenhardt, Franziska; Meier, Sandra; Paul, Torsten; O'Donovan, Michael Conlon; Mühleisen, Thomas W.; Schulze, Thomas G.; Nöthen, Markus M.; Cichon, Sven; Craddock, Nicholas John; Rietschel, Marcella

doi:10.1038/mp.2010.67

Cited by 31 publications

(27 citation statements)

References 8 publications

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“…Accumulated evidence suggests that the GABAergic system is associated with neurodevelopmental psychiatric disorders such as schizophrenia (Levitt et al, 2004;Lewis et al, 2005;Sanacora and Saricicek, 2007;Craddock et al, 2010;Breuer et al, 2011). Our results highlight the complexity of KCC2 transcription in the human DLPFC across normal human development and suggest that two truncated transcripts may be involved in the pathophysiology of schizophrenia, and perhaps affective disorders.…”

Section: Opposite Changes Of Exon6bmentioning

confidence: 71%

Transcript-Specific Associations of SLC12A5 (KCC2) in Human Prefrontal Cortex with Development, Schizophrenia, and Affective Disorders

Tao

Newburn

et al. 2012

J. Neurosci.

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The neuron-specific K ϩ -Cl Ϫ cotransporter SLC12A5, also known as KCC2, helps mediate the electrophysiological effects of GABA. The pattern of KCC2 expression during early brain development suggests that its upregulation drives the postsynaptic switch of GABA from excitation to inhibition. We previously found decreased expression of full-length KCC2 in the postmortem hippocampus of patients with schizophrenia, but not in the dorsolateral prefrontal cortex (DLPFC). Using PCR and rapid amplification of cDNA ends, we discovered several previously unrecognized alternative KCC2 transcripts in both human adult and fetal brain in addition to the previously identified full-length (NM_020708.3) and truncated (AK098371) transcripts. We measured the expression levels of four relatively abundant truncated splice variants, including three novel transcripts (⌬EXON6, EXON2B, and EXON6B) and one previously described transcript (AK098371), in a large human cohort of nonpsychiatric controls across the lifespan, and in patients with schizophrenia and affective disorders. In SH-SY5Y cell lines, these transcripts were translated into proteins and expressed at their predicted sizes. Expression of the EXON6B transcript is increased in the DLPFC of patients with schizophrenia (p ϭ 0.03) but decreased in patients with major depression (p ϭ 0.04). The expression of AK098371 is associated with a GAD1 single nucleotide polymorphism (rs3749034) that previously has been associated with GAD67 expression and risk for schizophrenia. Our data confirm the developmental regulation of KCC2 expression, and provide evidence that KCC2 transcripts are differentially expressed in schizophrenia and affective disorders. Alternate transcripts from KCC2 may participate in the abnormal GABA signaling in the DLPFC associated with schizophrenia.

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Section: Opposite Changes Of Exon6bmentioning

confidence: 71%

Transcript-Specific Associations of SLC12A5 (KCC2) in Human Prefrontal Cortex with Development, Schizophrenia, and Affective Disorders

Tao

Newburn

et al. 2012

J. Neurosci.

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“…In this respect it will be interesting to see whether, for example, the evidence of a relatively specific association with genetic markers in GABA A receptor genes [Craddock et al, 2010; Breuer et al, 2011] is fully confirmed. However, in order for schizoaffective-mania to be satisfactorily regarded as a partly independent disorder it will also be important to improve its inter-rater reliability, as discussed above.…”

Section: Discussionmentioning

confidence: 99%

“…There are ongoing calls for the term schizoaffective disorder to be abandoned [Lake and Hurwitz, 2007; Malhi et al, 2008]. On the other hand, the manic/bipolar subtype of Research Diagnostic Criteria (RDC) schizoaffective disorder [Spitzer et al, 1978] may be particularly useful in genetic association studies [Hamshere et al, 2009; Craddock et al, 2010; Breuer et al, 2011]. …”

Section: Introductionmentioning

confidence: 99%

A twin study of schizoaffective‐mania, schizoaffective‐depression, and other psychotic syndromes

Cardno

Rijsdijk

West

et al. 2011

American J of Med Genetics Pt B

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The nosological status of schizoaffective disorders remains controversial. Twin studies are potentially valuable for investigating relationships between schizoaffective-mania, schizoaffective-depression and other psychotic syndromes, but no such study has yet been reported. We ascertained 224 probandwise twin pairs (106 monozygotic, 118 same-sex dizygotic), where probands had psychotic or manic symptoms, from the Maudsley Twin Register in London (1948–1993). We investigated Research Diagnostic Criteria schizoaffective-mania, schizoaffective-depression, schizophrenia, mania and depressive psychosis primarily using a non-hierarchical classification, and additionally using hierarchical and data-derived classifications, and a classification featuring broad schizophrenic and manic syndromes without separate schizoaffective syndromes. We investigated inter-rater reliability and co-occurrence of syndromes within twin probands and twin pairs. The schizoaffective syndromes showed only moderate inter-rater reliability. There was general significant co-occurrence between syndromes within twin probands and monozygotic pairs, and a trend for schizoaffective-mania and mania to have the greatest co-occurrence. Schizoaffective syndromes in monozygotic probands were associated with relatively high risk of a psychotic syndrome occurring in their co-twins. The classification of broad schizophrenic and manic syndromes without separate schizoaffective syndromes showed improved inter-rater reliability, but high genetic and environmental correlations between the two broad syndromes. The results are consistent with regarding schizoaffective-mania as due to co-occurring elevated liability to schizophrenia, mania and depression; and schizoaffective-depression as due to co-occurring elevated liability to schizophrenia and depression, but with less elevation of liability to mania. If in due course schizoaffective syndromes show satisfactory inter-rater reliability and some specific etiological factors they could alternatively be regarded as partly independent disorders.

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“…Interestingly, GABA-A subunit genes have been linked to schizophrenia-like psychotic symptoms in bipolar disorder [87,88]. It has been shown that UBE3A plays a critical role in maturation of excitatory circuits and sensory experience-dependent synaptic plasticity [89,90].…”

Section: Parent-of-origin Effects and Schizophreniamentioning

confidence: 99%

From Prader–Willi Syndrome to Psychosis: Translating Parent-of-Origin Effects into Schizophrenia Research

et al. 2014

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Prader-Willi syndrome (PWS) is a relatively rare disorder that originates from paternally inherited deletions and maternal disomy (mUPD) within the 15q11-q13 region or alterations in the PWS imprinting center. Evidence is accumulating that mUPD underlies high prevalence of psychosis among PWS patients. Several genes involved in differentiation and survival of neurons as well as neurotransmission known to act in the development of PWS have been also implicated in schizophrenia. In this article, we provide an overview of genetic and epigenetic underpinnings of psychosis in PWS indicating overlapping points in the molecular background of PWS and schizophrenia. Simultaneously, we highlight the need for studies investigating genetic and epigenetic makeup of the 15q11-q13 in schizophrenia indicating promising candidate genes.

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Independent evidence for the selective influence of GABAA receptors on one component of the bipolar disorder phenotype

Cited by 31 publications

References 8 publications

Transcript-Specific Associations of SLC12A5 (KCC2) in Human Prefrontal Cortex with Development, Schizophrenia, and Affective Disorders

Transcript-Specific Associations of SLC12A5 (KCC2) in Human Prefrontal Cortex with Development, Schizophrenia, and Affective Disorders

A twin study of schizoaffective‐mania, schizoaffective‐depression, and other psychotic syndromes

From Prader–Willi Syndrome to Psychosis: Translating Parent-of-Origin Effects into Schizophrenia Research

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