Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

Mei, Lin; Nave, Klaus Armin

doi:10.1016/j.neuron.2014.06.007

Cited by 508 publications

(502 citation statements)

References 312 publications

(463 reference statements)

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“…These observations suggest that a proper level of Tmem108 needs to be maintained for homeostasis of spines. Altered level, either high or low, could serve as a pathophysiological mechanism (43).…”

Section: Discussionmentioning

confidence: 99%

Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus

Jiao

Sun

Bates

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia. dentate gyrus | spine | glutamatergic transmission | AMPA receptors | schizophrenia S chizophrenia is a disabling psychiatric disorder that affects 1% of the general population. It is thought to be a neurodevelopment disorder, as many symptoms appear or worsen during adolescence, a time of great transition and refinements in brain structure and function (1, 2). Consequently, patients display characteristic positive symptoms including delusions and hallucinations, negative symptoms including abnormal emotional reactivity and anhedonia and cognitive deficits. Underlying pathophysiological mechanisms have been explored extensively. The medial temporal lobe, including hippocampal dentate gyrus (DG), is thought to be involved in mediating aspects of psychosis and memory deficits in schizophrenia (3, 4). Impaired glutamatergic transmission in DG causes deficits in spatial coding, learning, and memory and emotion processing (5-7). However, detailed molecular mechanisms of DG dysfunction in schizophrenia remain unclear.Identification of risk genes in recent genetic studies has contributed to a better understanding of pathophysiological mechanisms of schizophrenia. Transmembrane protein 108 (TMEM108) has recently been linked with schizophrenia and alcoholism in genome-wide association studies (8, 9). In human, TMEM108 is located on chromosome 3q21-q22, a risk locus for bipolar disorder, schizophrenia and other psychosis (10, 11). In particular, an intronic single nucleotide polymorphism (SNP) (rs7624858) is associated with schizophrenia (8). These findings raise an important question regarding the physiological function of TMEM108 a...

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Section: Discussionmentioning

confidence: 99%

Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus

Jiao

Sun

Bates

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…Our results demonstrate that the transcription of ErbB4 does not change with age, but that shifts in ErbB4 splicing from the JM-b/CYT-2 to JM-a/CYT-1 variants occur in PV interneurons during adolescence in primate DLPFC. Activation of the ErbB4 signaling pathway by its ligand neuregulin 1 has been associated with multiple aspects of neuronal development (47), including the positive modulation of excitatory synapse number on PV interneurons (17,18). Similar to other genes that are involved in neurodevelopment (48), the functional consequence of ErbB4 signaling in PV neurons could be modulated by alternative splicing.…”

Section: Discussionmentioning

confidence: 99%

“…Excitatory synapses on PV interneurons are modulated in part by erb-b2 receptor tyrosine kinase 4 (ErbB4) (17,18). Activation of ErbB4 increases the number of excitatory synapses in a kinasedependent manner (19) and the loss of ErbB4 results in fewer excitatory synapses on PV interneurons (20).…”

mentioning

confidence: 99%

Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

Chung

Wills

Fish

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Working memory requires efficient excitatory drive to parvalbuminpositive (PV) interneurons in the primate dorsolateral prefrontal cortex (DLPFC). Developmental pruning eliminates superfluous excitatory inputs, suggesting that working memory maturation during adolescence requires pruning of excitatory inputs to PV interneurons. Therefore, we tested the hypothesis that excitatory synapses on PV interneurons are pruned during adolescence. The density of excitatory synapses, defined by overlapping vesicular glutamate transporter 1-positive (VGlut1+) and postsynaptic density 95-positive (PSD95+) puncta, on PV interneurons was lower in postpubertal relative to prepubertal monkeys. In contrast, puncta levels of VGlut1 and PSD95 proteins were higher in postpubertal monkeys and positively predicted activity-dependent PV levels, suggesting a greater strength of the remaining synapses after pruning. Because excitatory synapse number on PV interneurons is regulated by erb-b2 receptor tyrosine kinase 4 (ErbB4), whose function is influenced by alternative splicing, we tested the hypothesis that pruning of excitatory synapses on PV interneurons is associated with developmental shifts in ErbB4 expression and/or splicing. Pan-ErbB4 expression did not change, whereas the minor-to-major splice variant ratios increased with age. In cell culture, the major, but not the minor, variant increased excitatory synapse number on PV interneurons and displayed greater kinase activity than the minor variant, suggesting that the effect of ErbB4 signaling in PV interneurons is mediated by alternative splicing. Supporting this interpretation, in monkey DLPFC, higher minor-to-major variant ratios predicted lower PSD95+ puncta density on PV interneurons. Together, our findings suggest that ErbB4 splicing may regulate the pruning of excitatory synapses on PV interneurons during adolescence.synaptic pruning | parvalbumin interneuron | ErbB4 | alternative splicing | schizophrenia I n primates, certain complex cognitive processes, such as working memory, depend in part on the proper activation of specific neural circuits in the dorsolateral prefrontal cortex (DLPFC) (1). In both monkeys and humans, recruitment of DLPFC activity and performance during working memory tasks continue to improve through adolescence (2-4). During this period, excitatory synapses and their principal targets, pyramidal neuron dendritic spines, massively decline in number in the primate DLPFC (5-8). Synaptic pruning is thought to eliminate unwanted or imprecise connections and to strengthen the remaining connections (9, 10), suggesting that this process could contribute to the maturation of working memory function during adolescence.Working memory is thought to emerge from oscillatory activity of DLPFC neurons at gamma frequency (30-80 Hz) (11), which requires the activity of local GABAergic interneurons that express the calcium binding protein parvalbumin (PV) (12, 13). During working memory tasks, excitation from pyramidal neurons recruits PV interneurons, which in turn pro...

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“…Rapid advances in genetics have identified large numbers of putative disease-linked mutations on numerous genes (Govek et al 2005;Schubbert et al 2007;Pavlowsky et al 2012;Rauen 2013;Mei and Nave 2014;Siegert et al 2015;Volk et al 2015). However, how the disease-linked genes and mutations may differentially affect cellular functions and behavioral outputs remains poorly understood, primarily due to the time-and cost-prohibitive approaches for generating the large numbers of transgenic animal models required to understand the physiopathology of genes and their mutations (Govek et al 2005;Siegert et al 2015;Volk et al 2015).…”

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confidence: 99%

BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method

et al. 2017

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Rapid advances in genetics are linking mutations on genes to diseases at an exponential rate, yet characterizing the gene-mutation-cell-behavior relationships essential for precision medicine remains a daunting task. More than 350 mutations on BRaf are associated with various tumors, and ∼40 mutations are associated with the neurodevelopmental disorder cardio-facio-cutaneous syndrome (CFC). We developed a fast cost-effective lentivirus-based rapid gene replacement method to interrogate the physiopathology of BRaf and ∼50 disease-linked BRaf mutants, including all CFC-linked mutants. Analysis of simultaneous multiple patch-clamp recordings from 6068 pairs of rat neurons with validation in additional mouse and human neurons and multiple learning tests from 1486 rats identified BRaf as the key missing signaling effector in the common synaptic NMDA-R-CaMKII-SynGap-RasBRaf-MEK-ERK transduction cascade. Moreover, the analysis creates the original big data unveiling three general features of BRaf signaling. This study establishes the first efficient procedure that permits large-scale functional analysis of human disease-linked mutations essential for precision medicine.

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Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

Cited by 508 publications

References 312 publications

Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus

Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus

Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method

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