Nrg1 haploinsufficiency alters inhibitory cortical circuits

NEUROBIOLOGY OF DISEASE

卷:157

Article

Navarro-Gonzalez, Carmen¹  Carceller, Hector^1,5  Benito Vicente, Marina²  Serra, Irene³  Navarrete, Marta³  Dominguez-Canterla, Yaiza¹  Rodriguez-Prieto, Angela¹  Gonzalez-Manteiga, Ana¹  Fazzari, Pietro^1,4 

[1] CIPF Ctr Invest Principe Felipe, Lab Cort Circuits Hlth & Dis, Valencia, Spain

[2] Hosp Nacl Paraplej, Lab Resonancia Magnet Invest, Toledo, Spain

[3] CSIC, Inst Cajal, Madrid, Spain

[4] CSIC, Ctr Biol Mol Severo Ochoa, Madrid, Spain

[5] Univ Valencia, Neurobiol Unit, Dept Cell Biol Interdisciplinary Res Struct Biote, Valencia, Spain

关键词: Nrg1;    Schizophrenia;    Cortical neurons;    Inhibitory neurotransmission;    Magnetic resonance spectroscopy;   

DOI  :  10.1016/j.nbd.2021.105442

来源: Elsevier

【 摘 要 】

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.