On the Modulatory Roles of Neuregulins/ErbB Signaling on Synaptic Plasticity

Abstract

Neuregulins (NRGs) are a family of epidermal growth factor-related proteins, acting on tyrosine kinase receptors of the ErbB family. NRGs play an essential role in the development of the nervous system, since they orchestrate vital functions such as cell differentiation, axonal growth, myelination, and synapse formation. They are also crucially involved in the functioning of adult brain, by directly modulating neuronal excitability, neurotransmission, and synaptic plasticity. Here, we provide a review of the literature documenting the roles of NRGs/ErbB signaling in the modulation of synaptic plasticity, focusing on evidence reported in the hippocampus and midbrain dopamine (DA) nuclei. The emerging picture shows multifaceted roles of NRGs/ErbB receptors, which critically modulate different forms of synaptic plasticity (LTP, LTD, and depotentiation) affecting glutamatergic, GABAergic, and DAergic synapses, by various mechanisms. Further, we discuss the relevance of NRGs/ErbB-dependent synaptic plasticity in the control of brain processes, like learning and memory and the known involvement of NRGs/ErbB signaling in the modulation of synaptic plasticity in brain's pathological conditions. Current evidence points to a central role of NRGs/ErbB receptors in controlling glutamatergic LTP/LTD and GABAergic LTD at hippocampal CA3-CA1 synapses, as well as glutamatergic LTD in midbrain DA neurons, thus supporting that NRGs/ErbB signaling is essential for proper brain functions, cognitive processes, and complex behaviors. This suggests that dysregulated NRGs/ErbB-dependent synaptic plasticity might contribute to mechanisms underlying different neurological and psychiatric disorders.

Keywords: ErbB receptors; LTD; LTP; dopamine; hippocampus; midbrain dopamine neurons; neuregulins; synaptic plasticity.

Figure 1

NRG1 types and synthesis. (A) Diagram of structural differences of various NRG1 types. (B) Synthesis of NRGs’ mature forms is induced by different ADAMs and MMPs, with the release of soluble forms (as for example for NRG1 type I) or the exposure of the membrane-anchored EGF-like domain (as for NRG1 type III).

Figure 2

NRGs/ErbB signaling. (A) Diagram showing canonical ErbB signaling pathways activated by NRGs. (B) Scheme of non-canonical ErbB signaling modalities: (a) Non-canonical forward ErbB4 signaling: proteolytic cleavage of ErbB4 causes the release of its intracellular domain (ErbB4 ICD), which translocates to the nucleus, modulating gene expression; (b) Ecto-ErbB4 domain, containing the binding site of NRGs, is released by proteolytic cleavage of ErbB4 extracellular domain. Ecto-ErbB4 can bind pro-NRGs, thus interfering with NRGs canonical signaling or triggering NRG1 backward signaling; (c) NRG1 backward signaling: proteolytic cleavage of NRG1 (pro-NRG1s or membrane-anchored NRG1 type III) in the intracellular domain induces the release of NRG1 ICD, which triggers backward signaling by nuclear translocation and modulation of gene transcription.

Figure 3

NRGs/ErbB-dependent regulation of LTP in the hippocampal CA1 area. (A–C) Diagrams illustrating the cellular mechanisms underlying NRGs/ErbB-dependent impairment of LTP at hippocampal CA3–CA1 synapses. (A) NRG1-dependent activation of ErbB4 in GABAergic interneurons, by triggering GABA release, fosters the activation of GABA_A receptors expressed in CA1 pyramidal cells, thus reducing neuronal excitability and dampening LTP induction. (B) NRG1-induced ErbB4 activation on DAergic terminals inhibits DAT activity, thus increasing DA extracellular levels. The consequent activation of D4 receptors localized on CA1 pyramidal neurons impairs LTP induction/expression, via internalization of AMPARs. (C) NRG1-dependent ErbB4 activation in CA1 pyramidal neurons inhibits Src kinase and consequently NMDAR activity, thus reducing LTP expression.

Figure 4

Mechanisms underlying NRGs/ErbB-dependent regulation of mGluRI-LTD in the hippocampus. (A) NRG1-dependent activation of ErbB receptors in CA1 pyramidal neurons, by regulating mGluRI function, controls the LTD magnitude of AMPAR-mediated transmission. (B) NRG1, by activating ErbB receptors, reduces endocannabinoids (eCBs) levels, thus impairing the eCB-dependent LTD of GABAergic transmission, which is physiologically triggered by the eCB-mediated activation of CB1 located on presynaptic GABAergic terminals, controlling GABA release.

Figure 5

Mechanisms underlying NRG1/ErbB-dependent regulation of mGluRI-LTD in midbrain DA neurons. NRG1-dependent activation of ErbB receptors in SNpc DA neurons induces the synthesis of mGluR1 receptors, thus fostering mGluR1-LTD of AMPARs-mediated transmission, whereas inhibition of endogenous ErbB signaling causes mGluR1 internalization and consequent impairment of mGluR1-LTD.