Neuregulin-1/ErbB4 Signaling Regulates Visual Cortical Plasticity

Sun, Yanjun; Ikrar, Taruna; Davis, Melissa F.; Gong, Nian; Zheng, Xiaoting; Luo, Z. David; Lai, Cary; Mei, Lin; Holmes, Todd C.; Gandhi, Sunil; Xu, Xiangmin

doi:10.1016/j.neuron.2016.08.033

Cited by 100 publications

(149 citation statements)

References 51 publications

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“…Several proteins that regulate synaptic strength and/or number are highly enriched at excitatory synapses onto PV interneurons and impact the timing of the critical period and NRG1 (NARP: Chang et al, 2010; Gu et al, 2013, Pelkey et al, 2015; Gu et al, 2016; kaplan et al, 2016; Sun et al, 2016). Accordingly, NARP-deficient mice fail to initiate a critical period unless rescued by enhancing the strength of the inhibitory output or excitatory drive onto PV interneurons (Gu et al, 2013; Gu et al, 2016).…”

Section: Inhibition and Critical Period Inductionmentioning

confidence: 99%

Critical periods in amblyopia

2018

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The shift in ocular dominance (OD) of binocular neurons induced by monocular deprivation is the canonical model of synaptic plasticity confined to a postnatal critical period. Developmental constraints on this plasticity not only lend stability to the mature visual cortical circuitry but also impede the ability to recover from amblyopia beyond an early window. Advances with mouse models utilizing the power of molecular, genetic, and imaging tools are beginning to unravel the circuit, cellular, and molecular mechanisms controlling the onset and closure of the critical periods of plasticity in the primary visual cortex (V1). Emerging evidence suggests that mechanisms enabling plasticity in juveniles are not simply lost with age but rather that plasticity is actively constrained by the developmental up-regulation of molecular ‘brakes’. Lifting these brakes enhances plasticity in the adult visual cortex, and can be harnessed to promote recovery from amblyopia. The reactivation of plasticity by experimental manipulations has revised the idea that robust OD plasticity is limited to early postnatal development. Here, we discuss recent insights into the neurobiology of the initiation and termination of critical periods and how our increasingly mechanistic understanding of these processes can be leveraged toward improved clinical treatment of adult amblyopia.

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Section: Inhibition and Critical Period Inductionmentioning

confidence: 99%

Critical periods in amblyopia

2018

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“…First, we analyzed the density of PV + INs in a pre-CP stage (postnatal day P18), at the transition toward the opening of the CP (postnatal day P21), and at the end of the CP (postnatal day P35) (Fagiolini et al, 2004; Hooks and Chen, 2007; Sugiyama et al, 2008; Levelt and Hübener, 2012; Sun et al, 2016). While the density of PV + cells was similar in WT and mutant mice at P18 and P21 (two-way ANOVA: p > 0.05), null mice displayed a higher number of PV + INs at the closure of the CP (two-way ANOVA: p < 0.01; Bonferroni: P35 Cdkl5 +/y vs. Cdkl5 −/y p < 0.05; n = 5 for group; Figures 8A,B).…”

Section: Resultsmentioning

confidence: 99%

Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex

Pizzo

Gurgone

Castroflorio

et al. 2016

Front. Cell. Neurosci.

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Cyclin-dependent kinase-like 5 (CDKL5) mutations are found in severe neurodevelopmental disorders, including the Hanefeld variant of Rett syndrome (RTT; CDKL5 disorder). CDKL5 loss-of-function murine models recapitulate pathological signs of the human disease, such as visual attention deficits and reduced visual acuity. Here we investigated the cellular and synaptic substrates of visual defects by studying the organization of the primary visual cortex (V1) of Cdkl5−/y mice. We found a severe reduction of c-Fos expression in V1 of Cdkl5−/y mutants, suggesting circuit hypoactivity. Glutamatergic presynaptic structures were increased, but postsynaptic PSD-95 and Homer were significantly downregulated in CDKL5 mutants. Interneurons expressing parvalbumin, but not other types of interneuron, had a higher density in mutant V1, and were hyperconnected with pyramidal neurons. Finally, the developmental trajectory of pavalbumin-containing cells was also affected in Cdkl5−/y mice, as revealed by fainter appearance perineuronal nets at the closure of the critical period (CP). The present data reveal an overall disruption of V1 cellular and synaptic organization that may cause a shift in the excitation/inhibition balance likely to underlie the visual deficits characteristic of CDKL5 disorder. Moreover, ablation of CDKL5 is likely to tamper with the mechanisms underlying experience-dependent refinement of cortical circuits during the CP of development.

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“…NRG1, NRG3, and ERBB4 mutations and gene variants have been implicated in several neuropsychiatric diseases in humans, but are most frequently associated with schizophrenia in several ethnic groups (Stefansson et al, 2002;Chen et al, 2009;Kao et al, 2010;Greenwood et al, 2011;Morar et al, 2011;Hatzimanolis et al, 2013). ErbB4 is expressed in various neuronal types in the brain where it controls physiology and behavior (Li et al, 2007;Fazzari et al, 2010;Gu et al, 2016;Sun et al, 2016;Geng et al, 2017). In the neocortex and hippocampus, ErbB4 expression is restricted to GABAergic interneurons.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, ErbB4 has been assigned both a kinase-dependent and kinase-independent role in inhibitory synapse function (Krivosheya et al, 2008;Mitchell et al, 2013). Various responses of ErbB4 + interneurons to recombinant or transgenic overexpression of Nrg1 have been reported both in vitro and in vivo (Abe et al, 2011;Yin et al, 2013;Agarwal et al, 2014;Sun et al, 2016), and cortical ablation of Nrg1 can result in behavioral changes and unbalanced excitatory-inhibitory neurotransmission (Agarwal et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Neuregulin 3 promotes excitatory synapse formation on hippocampal interneurons

et al. 2018

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Hippocampal GABAergic interneurons are crucial for cortical network function and have been implicated in psychiatric disorders. We show here that Neuregulin 3 (Nrg3), a relatively little investigated low‐affinity ligand, is a functionally dominant interaction partner of ErbB4 in parvalbumin‐positive (PV) interneurons. Nrg3 and ErbB4 are located pre‐ and postsynaptically, respectively, in excitatory synapses on PV interneurons in vivo. Additionally, we show that ablation of Nrg3 results in a similar phenotype as the one described for ErbB4 ablation, including reduced excitatory synapse numbers on PV interneurons, altered short‐term plasticity, and disinhibition of the hippocampal network. In culture, presynaptic Nrg3 increases excitatory synapse numbers on ErbB4+ interneurons and affects short‐term plasticity. Nrg3 mutant neurons are poor donors of presynaptic terminals in the presence of competing neurons that produce recombinant Nrg3, and this bias requires postsynaptic ErbB4 but not ErbB4 kinase activity. Furthermore, when presented by non‐neuronal cells, Nrg3 induces postsynaptic membrane specialization. Our data indicate that Nrg3 provides adhesive cues that facilitate excitatory neurons to synapse onto ErbB4+ interneurons.

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Neuregulin-1/ErbB4 Signaling Regulates Visual Cortical Plasticity

Cited by 100 publications

References 51 publications

Critical periods in amblyopia

Critical periods in amblyopia

Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex

Neuregulin 3 promotes excitatory synapse formation on hippocampal interneurons

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