Neuregulin 1/ErbB signalling modulates hippocampal mGluRI-dependent LTD and object recognition memory

The neurotrophic factors neuregulins (NRGs) and their receptors, ErbB tyrosine kinases, regulate neurotransmission, synaptic plasticity and cognitive functions and their alterations have been associated to different neuropsychiatric disorders. Group 1 metabotropic glutamate receptors (mGluRl)-dependent mechanisms are also altered in animal models of neuropsychiatric diseases, especially mGluRl-induced glutamatergic long-term depression (mGluRl-LTD), a form of synaptic plasticity critically involved in learning and memory. Despite this evidence, a potential link between NRGs/ErbB signalling and mGluRl-LTD has never been considered.Here, we aimed to test the hypothesis that NRGs/ErbB signalling regulates mGluRI functions in the hippocampus, thus controlling CA1 pyramidal neurons excitability and synaptic plasticity as well as mGluRl-dependent behaviors. We investigated the functional interaction between NRG1/ErbB signalling and mGluRl in hippocampal CA1 pyramidal neurons, by analyzing the effect of a pharmacological modulation of NRG1/ErbB signalling on the excitation of pyramidal neurons and on the LTD at CA3-CA1 synapses induced by an mGluRl agonist. Furthermore, we verified the involvement of ErbB signalling in mGluRl-dependent learning processes, by evaluating the consequence of an intrahippocampal in vivo injection of a pan-ErbB inhibitor in the object recognition test in mice, a learning task dependent on hippocampal mGluRl.We found that NRG1 potentiates mGluRl-dependent functions on pyramidal neurons excitability and synaptic plasticity at CA3-CA1 synapses. Further, endogenous ErbB signalling per se regulates, through mGluRl, neuronal excitability and LTD in CA1 pyramidal neurons, since ErbB inhibition reduces mGluRl-induced neuronal excitation and mGluRl-LTD. In vivo intrahippocampal injection of the ErbB inhibitor, PD158780, impairs mGluRl-LTD at CA3-CA1 synapses and affects the exploratory behavior in the object recognition test.Thus, our results identify a key role for NRG1/ErbB signalling in the regulation of hippocampal mGluRl-dependent synaptic and cognitive functions, whose alteration might contribute to the pathogenesis of different brain diseases. (C) 2018 Elsevier Ltd. All rights reserved.