Nrg1 haploinsufficiency alters inhibitory cortical circuits
Neuregulin 1 (NRG1) and its receptor ERBB4 are schizophrenia (SZ) risk genes that control the development of both excitatory and inhibitory cortical circuits. Most studies focused on the characterization ErbB4 deficient mice. However, ErbB4 deletion concurrently perturbs the signaling of Nrg1 and Ne...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-09-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996121001911 |
| _version_ | 1819097653164638208 |
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| author | Carmen Navarro-Gonzalez Héctor Carceller Marina Benito Vicente Irene Serra Marta Navarrete Yaiza Domínguez-Canterla Ángela Rodríguez-Prieto Ana González-Manteiga Pietro Fazzari |
| author_facet | Carmen Navarro-Gonzalez Héctor Carceller Marina Benito Vicente Irene Serra Marta Navarrete Yaiza Domínguez-Canterla Ángela Rodríguez-Prieto Ana González-Manteiga Pietro Fazzari |
| author_sort | Carmen Navarro-Gonzalez |
| collection | DOAJ |
| description | Neuregulin 1 (NRG1) and its receptor ERBB4 are schizophrenia (SZ) risk genes that control the development of both excitatory and inhibitory cortical circuits. Most studies focused on the characterization ErbB4 deficient mice. However, ErbB4 deletion concurrently perturbs the signaling of Nrg1 and Neuregulin 3 (Nrg3), another ligand expressed in the cortex. In addition, NRG1 polymorphisms linked to SZ locate mainly in non-coding regions and they may partially reduce Nrg1 expression.Here, to study the relevance of Nrg1 partial loss-of-function in cortical circuits we characterized a recently developed haploinsufficient mouse model of Nrg1 (Nrg1tm1Lex). These mice display SZ-like behavioral deficits. The cellular and molecular underpinnings of the behavioral deficits in Nrg1tm1Lex mice remain to be established.With multiple approaches including Magnetic Resonance Spectroscopy (MRS), electrophysiology, quantitative imaging and molecular analysis we found that Nrg1 haploinsufficiency impairs the inhibitory cortical circuits. We observed changes in the expression of molecules involved in GABAergic neurotransmission, decreased density of Vglut1 excitatory buttons onto Parvalbumin interneurons and decreased frequency of spontaneous inhibitory postsynaptic currents. Moreover, we found a decreased number of Parvalbumin positive interneurons in the cortex and altered expression of Calretinin. Interestingly, we failed to detect other alterations in excitatory neurons that were previously reported in ErbB4 null mice suggesting that the Nrg1 haploinsufficiency does not entirely phenocopies ErbB4 deletions.Altogether, this study suggests that Nrg1 haploinsufficiency primarily affects the cortical inhibitory circuits in the cortex and provides new insights into the structural and molecular synaptic impairment caused by NRG1 hypofunction in a preclinical model of SZ. |
| first_indexed | 2024-12-22T00:18:30Z |
| format | Article |
| id | doaj.art-26c10ea82df1412d8fd84ffb7e3c1d0f |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T00:18:30Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-26c10ea82df1412d8fd84ffb7e3c1d0f2022-12-21T18:45:14ZengElsevierNeurobiology of Disease1095-953X2021-09-01157105442Nrg1 haploinsufficiency alters inhibitory cortical circuitsCarmen Navarro-Gonzalez0Héctor Carceller1Marina Benito Vicente2Irene Serra3Marta Navarrete4Yaiza Domínguez-Canterla5Ángela Rodríguez-Prieto6Ana González-Manteiga7Pietro Fazzari8Lab of Cortical Circuits in Health and Disease, CIPF Centro de Investigación Príncipe Felipe, Valencia, SpainLab of Cortical Circuits in Health and Disease, CIPF Centro de Investigación Príncipe Felipe, Valencia, SpainLaboratorio Resonancia Magnética de Investigación, Hospital Nacional de Parapléjicos, Toledo, SpainConsejo Superior de Investigaciones Científicas (CSIC), Instituto Cajal, Madrid, SpainConsejo Superior de Investigaciones Científicas (CSIC), Instituto Cajal, Madrid, SpainLab of Cortical Circuits in Health and Disease, CIPF Centro de Investigación Príncipe Felipe, Valencia, SpainLab of Cortical Circuits in Health and Disease, CIPF Centro de Investigación Príncipe Felipe, Valencia, SpainLab of Cortical Circuits in Health and Disease, CIPF Centro de Investigación Príncipe Felipe, Valencia, SpainLab of Cortical Circuits in Health and Disease, CIPF Centro de Investigación Príncipe Felipe, Valencia, Spain; Consejo Superior de Investigaciones Científicas (CSIC), Centro de Biología Molecular Severo Ochoa, Madrid, Spain; Corresponding author at: Laboratory of Cortical Circuits in Health and Disease, I-64, CIPF, Centro de Investigación Príncipe Felipe, C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain.Neuregulin 1 (NRG1) and its receptor ERBB4 are schizophrenia (SZ) risk genes that control the development of both excitatory and inhibitory cortical circuits. Most studies focused on the characterization ErbB4 deficient mice. However, ErbB4 deletion concurrently perturbs the signaling of Nrg1 and Neuregulin 3 (Nrg3), another ligand expressed in the cortex. In addition, NRG1 polymorphisms linked to SZ locate mainly in non-coding regions and they may partially reduce Nrg1 expression.Here, to study the relevance of Nrg1 partial loss-of-function in cortical circuits we characterized a recently developed haploinsufficient mouse model of Nrg1 (Nrg1tm1Lex). These mice display SZ-like behavioral deficits. The cellular and molecular underpinnings of the behavioral deficits in Nrg1tm1Lex mice remain to be established.With multiple approaches including Magnetic Resonance Spectroscopy (MRS), electrophysiology, quantitative imaging and molecular analysis we found that Nrg1 haploinsufficiency impairs the inhibitory cortical circuits. We observed changes in the expression of molecules involved in GABAergic neurotransmission, decreased density of Vglut1 excitatory buttons onto Parvalbumin interneurons and decreased frequency of spontaneous inhibitory postsynaptic currents. Moreover, we found a decreased number of Parvalbumin positive interneurons in the cortex and altered expression of Calretinin. Interestingly, we failed to detect other alterations in excitatory neurons that were previously reported in ErbB4 null mice suggesting that the Nrg1 haploinsufficiency does not entirely phenocopies ErbB4 deletions.Altogether, this study suggests that Nrg1 haploinsufficiency primarily affects the cortical inhibitory circuits in the cortex and provides new insights into the structural and molecular synaptic impairment caused by NRG1 hypofunction in a preclinical model of SZ.http://www.sciencedirect.com/science/article/pii/S0969996121001911Nrg1SchizophreniaCortical neuronsInhibitory neurotransmissionMagnetic resonance spectroscopy |
| spellingShingle | Carmen Navarro-Gonzalez Héctor Carceller Marina Benito Vicente Irene Serra Marta Navarrete Yaiza Domínguez-Canterla Ángela Rodríguez-Prieto Ana González-Manteiga Pietro Fazzari Nrg1 haploinsufficiency alters inhibitory cortical circuits Neurobiology of Disease Nrg1 Schizophrenia Cortical neurons Inhibitory neurotransmission Magnetic resonance spectroscopy |
| title | Nrg1 haploinsufficiency alters inhibitory cortical circuits |
| title_full | Nrg1 haploinsufficiency alters inhibitory cortical circuits |
| title_fullStr | Nrg1 haploinsufficiency alters inhibitory cortical circuits |
| title_full_unstemmed | Nrg1 haploinsufficiency alters inhibitory cortical circuits |
| title_short | Nrg1 haploinsufficiency alters inhibitory cortical circuits |
| title_sort | nrg1 haploinsufficiency alters inhibitory cortical circuits |
| topic | Nrg1 Schizophrenia Cortical neurons Inhibitory neurotransmission Magnetic resonance spectroscopy |
| url | http://www.sciencedirect.com/science/article/pii/S0969996121001911 |
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