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.

Insights on the Functional Interaction between Group 1 Metabotropic Glutamate Receptors (mGluRI) and ErbB Receptors

“…Additionally, in midbrain DA neurons, mGluR1-activated currents and mGluR1-induced intracellular Ca 2+ mobilization are impaired by a TKs inhibitor, tyrphostin B-52, that inhibits EGFR, and few other TKs including avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) [42]. More recently, additional insights on the functional relevance of the RTKs on mGluRI have been provided from studies from our group proving that proper mGluRI function relies on an intact basal activity of RTKs of ErbB family, activated by the neurotrophic factors neuregulins (NRGs) [51][52][53][54]. As will be discussed below, after an introductive paragraph on ErbB receptors and their ligands, mGluRI activity is tightly dependent on ErbB activity, and the functional interaction between mGluRI and ErbB has various implications in the regulation of excitability, neurotransmission, synaptic plasticity, and learning processes [51][52][53][54].…”

“…ErbB1 is the epidermal growth factor (EGF) receptor (EGFR), whereas ErbB2, ErbB3, and ErbB4 are receptors of NRGs. ErbB receptors are functional as dimers, and distinct ErbB subtypes can differently participate in the formation of homodimeric or heterodimeric complexes, based on their distinctive properties, having each ErbB subtype a unique profile in relation to ligand binding properties and affinities, or catalytic activity [54][55][56]. Ligands for ErbB1-the EGF family ligands-are, besides EGF, transforming growth factor alpha (TGFα), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), epiregulin (EPR5), betacellulin, (BTC), and epigen (EPG).…”

“…Ligands for ErbB1-the EGF family ligands-are, besides EGF, transforming growth factor alpha (TGFα), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), epiregulin (EPR5), betacellulin, (BTC), and epigen (EPG). The family of NRGs includes various components: NRG1 (also known as heregulin (HRG), Neu differentiation factor (NDF), acetylcholine receptor-inducing activity (ARIA), glial growth factor (GGF), or sensory and motor neuron-derived factor (SMDF)), NRG2 (also called NTAK), NRG3, NRG4, NRG5 (also known as tomoregulin), and NRG6 (also known as neuroglycan C) [54][55][56][57]. Different NRGs types display diverse affinity for ErbB3 and ErbB4, while none directly bind ErbB2, which is thus an indirect NRGs receptor, indirectly activated by NRGs through the others NRGs-binding subunits (ErbB3 and ErbB4).…”

“…ERK also phosphorylates cytoskeletal proteins, like actin, which promote cell motility, or regulators of cell division and organelle movement, as well as mitochondrial targets such as Bcl2 that render cells resistant to apoptosis. Other NRGs/ErbB-activated pathways, like the PLC-PKC or c-Abl, JNK, CDK5, Lyn, and Pyk2, are mainly involved in gene expression regulation, by activation of transcriptional factors like c-Fos, Elk1, STAT, c-Jun, and c-Myc [54,56,61] (Figure 3).…”

“…proteins acting as adaptors or effectors of ErbB signaling pathways. Typical ErbB-activated pathways are PI3K-Akt-mTOR, Ras-Raf-MEK-ERK, and PLC-PKC, as well as kinases like c-Abl, JNK, CDK5, Lyn, Pyk2, and glycogen synthase kinase-3 (GSK-3) [54,56,61] (Figure 3). The activation of PI3K-Akt-mTOR, and GSK-3, downstream to Akt, has been associated to NRGs/ErbB-dependent mechanisms that initiate protein synthesis and cause neuronal growth and survival.…”