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.
Highlights
Neuregulins (NRGs) are a family of neurotrophic factors, which are essential for proper development of the peripheral and central nervous system, as well as adult brain homeostasis
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
Regarding peculiar mechanisms that might control the synthesis of specific NRGs, it has been reported that neuregulin 1 (NRG1) types I and II or NRG2 accumulate as pro-forms on cell bodies and are released by matrix metalloproteinases (MMPs), in an activity dependent manner, whereas NRG1 type III and NRG3 seem to be constitutively processed by BACE and accumulate on axons where they interact with ErbB in juxtacrine mode [37]
Summary
Neuregulins (NRGs) are a family of neurotrophic factors, which are essential for proper development of the peripheral and central nervous system, as well as adult brain homeostasis. NRGs were discovered more than 25 years ago, independently by four groups that identified a protein, recognized as the first member of the NRGs family, neuregulin 1 (NRG1), as a factor able to activate ErbB2 tyrosine kinase receptors (called heregulin or neu differentiation factor (NDF)) [1,2,3], to induce proliferation of Schwann cells (called glial growth factor (GGF)) [4,5,6,7,8], or to stimulate the synthesis of acetylcholine receptors at developing neuromuscular junctions (NMJ) (called acetylcholine receptor inducing activity (ARIA)) [9] Such a diverse array of names and corresponding functions of NRG1 are indicative of the versatility and importance of NRGs in human brain. Available evidence supports diverse mechanisms engaged by NRGs/ErbB receptors in the regulation of long term modifications of synaptic transmission in these brain areas, depicting a complex scenario involving either presynaptic or postsynaptic NRGs-mediated mechanisms, which affect glutamatergic, GABAergic, and DAergic transmission
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