Neuregulin 1 Promotes Excitatory Synapse Development and Function in GABAergic Interneurons

Ting, A.K.L.; Chen, Yongjun; Wen, Lei; Yin, Dong Min; Shen, Chengyong; Tao, Yanmei; Liu, Xihui; Xiong, Wen Cheng; Mei, Lin

doi:10.1523/jneurosci.2538-10.2011

Cited by 203 publications

(175 citation statements)

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“…These results suggest that NRG1 slowly promotes developmental maturation of and/or synapse formation at excitatory nerve terminals in this neuronal population. This explanation is in accordance with the reports that the activation of ErbB4 promotes presynaptic development of excitatory input synapses in hippocampal pyramidal cells Krivosheya et al, 2008) as well as in cultured cortical GABAergic neurons (Ting et al, 2011).…”

Section: Acute and Subchronic Effects Of Nrg1 On Excitatory Input Synsupporting

confidence: 93%

Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex

Abe¹,

Namba²,

Kato³

et al. 2011

J. Neurosci.

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Neuregulin-1 (NRG1) signaling is thought to contribute to both neuronal development and schizophrenia neuropathology. Here, we describe the developmental effects of excessive peripheral NRG1 signals on synaptic activity and AMPA receptor expression of GABAergic interneurons in postnatal rodent neocortex. A core peptide common to all NRG1 variants (eNRG1) was subcutaneously administered to mouse pups. Injected eNRG1 penetrated the blood-brain barrier and activated ErbB4 NRG1 receptors in the neocortex, in which ErbB4 mRNA is predominantly expressed by parvalbumin-positive GABAergic interneurons. We prepared neocortical slices from juvenile mice that were receiving eNRG1 subchronically and recorded inhibitory synaptic activity from layer V pyramidal neurons. Postnatal eNRG1 treatment significantly enhanced polysynaptic IPSCs, although monosynaptic IPSCs were not affected. Examination of excitatory inputs to parvalbumin-containing GABAergic interneurons revealed that eNRG1 treatment significantly increased AMPA-triggered inward currents and the amplitudes and frequencies of miniature EPSCs (mEPSCs). Similar effects on mEPSCs were observed in mice treated with a soluble, full-length form of NRG1 type I. Consistent with the electrophysiologic data, expression of the AMPA receptor GluA1 (i.e., GluR1, GluRA) was upregulated in the postsynaptic density/cytoskeletal fraction prepared from eNRG1-treated mouse neocortices. Cortical GABAergic neurons cultured with eNRG1 exhibited a significant increase in surface GluA1 immunoreactivity at putative synaptic sites on their dendrites. These results indicate that NRG1 circulating in the periphery influences postnatal development of synaptic AMPA receptor expression in cortical GABAergic interneurons and may play a role in conditions characterized by GABA-associated neuropathologic processes.

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Section: Acute and Subchronic Effects Of Nrg1 On Excitatory Input Synsupporting

confidence: 93%

Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex

Abe¹,

Namba²,

Kato³

et al. 2011

J. Neurosci.

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“…For images containing primary neurons, the VGlut1+ and PSD95+ puncta were masked using the binary threshold function in NIS-Elements AR software (Nikon). The proximal dendrites were defined as neurites containing PSD95+ puncta within 30 μm from the PV+/DsRed+ cell body as previously characterized (19). The cell body and one randomly selected proximal dendrite from each sampled PV+/DsRed+ neuron were manually masked.…”

Section: Methodsmentioning

confidence: 99%

“…ErbB4 kinase activity is necessary for excitatory synapse formation (19,29). To investigate whether the differential effect of ErbB4 splice variants reflects differences in their kinase activity, we expressed ErbB4 JM-a/CYT-1 or JM-b/ CYT-2 variant in HEK-293 cells and assessed phosphorylation levels of ErbB4 in response to neuregulin 1 stimulation.…”

Section: Differential Kinase Activity Of Erbb4 Splice Variants In Resmentioning

confidence: 99%

“…Finally, to investigate whether the effect of ErbB4 splicing shifts on the number of excitatory inputs to PV neurons is reflected during pruning in primate DLPFC, we assessed the relationships between ErbB4 splicing shifts and the density of excitatory synapses on PV interneurons across all monkeys. Previous studies have demonstrated that ErbB4 signaling regulates the formation of excitatory synapses on PV interneurons primarily by its effect on synaptic recruitment of PSD95 (19,29,43). Consistent with these findings, the JM-a:JM-b (R = −0.612, P = 0.026) and CYT-1:CYT-2 (R = −0.642, P = 0.018) ratios were both significantly negatively correlated with the mean density of PSD95+ puncta on PV cell bodies across all animals.…”

Section: Association Between Erbb4 Splicing Shifts and Pruning Of Excmentioning

confidence: 99%

“…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). Moreover, ErbB4 transcripts are alternatively spliced at two loci, generating four different splice variants with distinct downstream signaling pathways (21).…”

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confidence: 99%

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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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Monosynaptic inputs to ErbB4‐expressing inhibitory neurons in mouse primary somatosensory cortex

Choi

Callaway

2011

J of Comparative Neurology

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Previous reports have described inputs to the somatosensory cortex (S1) in mouse or rat using retrograde or anterograde tracers. Such studies do not, however, reveal which particular cell types within the S1 cortex receive direct monosynaptic connections from these input sources. Here we describe the monosynaptic inputs to a subpopulation of mouse S1 inhibitory neurons that express ErbB4. We used a previously described “bridge protein”, composed of the ErbB4 ligand, neuregulin (NRG1), fused to the avian viral receptor TVB (TVB-NRG1), along with EnvB pseudotyped lentivirus (LV) and rabies virus (RV), to selectively co-infect ErbB4 expressing neurons (Choi et al., 2010). The RV had its glycoprotein gene deleted and replaced with mCherry, so that infected cells express mCherry and the virus cannot spread without provision of rabies glycoprotein (RG) by transcomplementation. The LV encoded and expressed RG to allow transcomplementation in co-infected neurons, so that the RV could spread transsynaptically and label their direct monosynaptic inputs. The RV could not spread beyond the direct inputs, due to the lack of RG in presynaptic cells. This method revealed long-range connections from thalamus, nucleus basalis, Raphe, and distant cortical areas, including ipsilateral motor, secondary somatosensory, retrosplenial, and perirhinal cortex and contralateral S1. In addition, local connections from ipsilateral pyramidal neurons within S1 were labeled. These input sources account for all of the known inputs to S1 described with standard tracers, suggesting that the subpopulation of ErbB4 positive inhibitory neurons infected using the TVB-NRG1 bridge protein receives inputs indiscriminately from S1 input sources.

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Neuregulin 1 Promotes Excitatory Synapse Development and Function in GABAergic Interneurons

Cited by 203 publications

References 53 publications

Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex

Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex

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

Monosynaptic inputs to ErbB4‐expressing inhibitory neurons in mouse primary somatosensory cortex

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