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Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression.

ABSTRACT: Alternative splicing of ErbB4 transcripts is dysregulated in the dorsolateral prefrontal cortex in schizophrenia. ErbB4 regulates the activity of parvalbumin interneurons, and therefore dysregulated ErbB4 splicing could contribute to lower parvalbumin interneuron activity and consequently lower parvalbumin levels in schizophrenia. However, ErbB4 is also present in calretinin interneurons, which are not affected in schizophrenia. Therefore, the authors hypothesized that dysregulated ErbB4 splicing occurs selectively in parvalbumin interneurons and is associated with lower parvalbumin levels in schizophrenia.Tissue samples enriched in calretinin and parvalbumin interneurons were laser microdissected from dorsolateral prefrontal cortex layers 2 and 4, respectively, from matched pairs of schizophrenia and comparison subjects. Transcript levels for pan-ErbB4, four ErbB4 splicing variants (JM-a, JM-b, CYT-1, CYT-2), parvalbumin, and calretinin were quantified by quantitative polymerase chain reaction (qPCR) in each layer. Transcript levels for myocardial infarction associated transcript (MIAT), which regulates ErbB4 splicing, were quantified in gray matter by qPCR and in parvalbumin interneurons by microarray.Calretinin and parvalbumin mRNAs were preferentially expressed in layers 2 and 4, respectively. In schizophrenia subjects, lower parvalbumin levels, higher CYT-1 and JM-a levels, and lower CYT-2 and JM-b levels were detected selectively in layer 4. In layer 4, the JM-a/JM-b ratio was inversely correlated with parvalbumin levels in schizophrenia subjects. MIAT levels were preferentially higher in parvalbumin interneurons in schizophrenia subjects.These findings suggest that elevated MIAT expression alters ErbB4 splicing selectively in parvalbumin interneurons in schizophrenia. Dysregulated ErbB4 splicing in schizophrenia may contribute to lower activity of parvalbumin interneurons and an activity-dependent down-regulation of parvalbumin expression.

SUBMITTER: Chung DW

PROVIDER: S-EPMC5242561 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression.

Chung Daniel W DW Volk David W DW Arion Dominique D Zhang Yun Y Sampson Allan R AR Lewis David A DA

The American journal of psychiatry 20150904 1

<h4>Objective</h4>Alternative splicing of ErbB4 transcripts is dysregulated in the dorsolateral prefrontal cortex in schizophrenia. ErbB4 regulates the activity of parvalbumin interneurons, and therefore dysregulated ErbB4 splicing could contribute to lower parvalbumin interneuron activity and consequently lower parvalbumin levels in schizophrenia. However, ErbB4 is also present in calretinin interneurons, which are not affected in schizophrenia. Therefore, the authors hypothesized that dysregul ...[more]

PMID: 26337038

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Project description:BackgroundFragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice.MethodsWe used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons.ResultsDe novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities.LimitationsThe mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors.ConclusionsOur findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS.

Dataset Information

Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression.

Publications

Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression.

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