ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation

Abstract

Neuregulin 1 (NRG1) is a trophic factor that acts by stimulating ErbB receptor tyrosine kinases and has been implicated in neural development and synaptic plasticity. In this study, we investigated mechanisms of its suppression of long-term potentiation (LTP) in the hippocampus. We found that NRG1 did not alter glutamatergic transmission at SC-CA1 synapses but increased the GABA A receptormediated synaptic currents in CA1 pyramidal cells via a presynaptic mechanism. Inhibition of GABA A receptors blocked the suppressing effect of NRG1 on LTP and prevented ecto-ErbB4 from enhancing LTP, implicating a role of GABAergic transmission. To test this hypothesis further, we generated parvalbumin (PV)-Cre;ErbB4 −/− mice in which ErbB4, an NRG1 receptor in the brain, is ablated specifically in PV-positive interneurons. NRG1 was no longer able to increase inhibitory postsynaptic currents and to suppress LTP in PV-Cre; ErbB4 −/− hippocampus. Accordingly, contextual fear conditioning, a hippocampus-dependent test, was impaired in PV-Cre;ErbB4 −/− mice. In contrast, ablation of ErbB4 in pyramidal neurons had no effect on NRG1 regulation of hippocampal LTP or contextual fear conditioning. These results demonstrate a critical role of ErbB4 in PV-positive interneurons but not in pyramidal neurons in synaptic plasticity and support a working model that NRG1 suppresses LTP by enhancing GABA release. Considering that NRG1 and ErbB4 are susceptibility genes of schizophrenia, these observations contribute to a better understanding of how abnormal NRG1/ErbB4 signaling may be involved in the pathogenesis of schizophrenia. N euregulin 1 (NRG1) is a trophic factor that acts by activating ErbB receptor tyrosine kinases, including ErbB4. NRG1 signaling has been implicated in various steps in neural development, including neuron migration, axon guidance, synapse formation, and expression of neurotransmitter receptors (1). Studies of NRG1 have attracted much attention because both NRG1 and ErbB4 were identified as susceptibility genes of schizophrenia and NRG1 and ErbB4 mutant mice show schizophrenia-relevant behaviors (1-4).Recent studies suggest that NRG1 plays a role in neurotransmission and synaptic plasticity (1). NRG1 has been shown to suppress the induction of LTP acutely at Schaffer collateral (SC)-CA1 synapses in adult rodent hippocampus (5-8), but it has no effect on basal synaptic transmission (5, 7, 9). NRG1 regulation of long-term potentiation (LTP) requires ErbB4 (8); however, underlying mechanisms remain unclear. In vitro studies suggest that NRG1 may alter functions of pyramidal neurons and glutamatergic transmission. For example, it could suppress NMDA receptor (NMDAR) currents in prefrontal cortical (PFC) neurons in culture (10). NRG1 was shown to stimulate internalization of surface AMPA receptors (AMPARs) in dissociated hippocampal neurons (11). Moreover, changes in ErbB4 levels in neonatal hippocampal slices alter dendritic spine size and AMPA synaptic currents (12). Conversely, ErbB4 expression is largely restricted to ...

Processing of Neuregulin-1 by Neuropsin Regulates GABAergic Neuron to Control Neural Plasticity of the Mouse Hippocampus

“…9A-C]. This observation is consistent with previous reports demonstrating a suppressive effect of mNRG-1 on LTP (Huang et al, 2000;Ma et al, 2003;Iyengar and Mott, 2008;Pitcher et al, 2008;Chen et al, 2010;Pitcher et al, 2011). By contrast, bath application of recombinant NRG-1 177-246 had no effect on basal synaptic strength in wild-type or neuropsin knock-out slices (see Fig.…”

“…LTP was induced by a single tetanic stimulation, which consisted of 100 stimuli delivered at 100 Hz at the test intensity. Recombinant human NRG-1 EGF-like domain [NRG-1 177-246 , a functional NRG-1 (Bjarnadottir et al, 2007;Chen et al, 2010;Pitcher et al, 2011); the EGF-like domain consists exactly of amino acid residues 177-246] (Peprotech) was applied to slices at 0.5 or 10 nM for 20 or 35 min after a stable baseline had been attained. ACSF was also supplemented as indicated with AG1478 (5 M; LC Laboratories) or bicuculline methiodide (Bicu) (10 M; Santa Cruz Biotechnology).…”

“…Recombinant NRG-1 has been reported to suppress protein synthesis-independent Schaffer-collateral LTP (E-LTP) in CA1 hippocampal synapses in the mouse brain (Huang et al, 2000;Ma et al, 2003;Kwon et al, 2005;Iyengar and Mott, 2008;Pitcher et al, 2008;Chen et al, 2010;Pitcher et al, 2011). Interestingly, previous studies have contradicted this suppressive effect and reported that NRG-1 potentiates tetanus-induced LTP in heterozygous mice deficient for the EGF domain of NRG-1, Nrg1(⌬EGF ) ϩ/Ϫ , although it had a similar suppressive effect on E-LTP in normal mouse hippocampal slices (Bjarnadottir et al, 2007;Role and Talmage, 2007).…”

Finding a druggable target for schizophrenia

“…It is worth mentioning that downregulation and overexpression of NRG1 cause similar behavioral phenotypes, including impaired recognition memory, hyperactivity, and enhanced exploratory phenotype (17)(18)(19). Some of these behavioral deficits are also found in ERBB4 lossof-function experimental models (11,13). These results draw our attention to the need to be cautious in our interpretation of the mouse models.…”

“…1). Genetic manipulations of NRG1/ERBB4 signaling in animal models lead to abnormal GABA neural circuit development and plasticity (11)(12)(13) and cause behavior alterations associated with attention and cognitive deficits, such as prepulse inhibition (PPI) deficits, working memory impairment, and hyperactivity (11,13). PI3K function has also been linked to neural circuit development, synaptic plasticity, and cognitive function (14,15).…”