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In addition, the amplitude and frequency of miniature EPSCs (mEPSCs) were depressed in CK?Nrg1f/f mutants ( Figures 2I�C2K), whereas mIPSC amplitude was enhanced ( Figures 2L and 2M) and mIPSC frequency was depressed ( Figures 2L and 2N). In summary, postnatal NRG1 deficiency in projection neurons shifts the balance of excitatory-inhibitory neurotransmission toward enhanced inhibition and leads to reduced LTP in the hippocampus at later stages. To identify NRG1 functions during the establishment of neuronal circuits, we performed a subset of the above experiments in Emx1-Cre?Nrg1f/f Selleck Osimertinib mutants (Emx?Nrg1f/f), in which NRG1 is eliminated in projection neurons and glial cells beginning at embryonic day (E) 10 ( Figure?3A; Gorski et?al., 2002). Emx?Nrg1f/f mutants were born at the expected Mendelian frequency and survived into adulthood. Despite a reduction of cortical NRG1 protein levels by ?80% in Emx?Nrg1f/f mutants ( Figure?3B), gray and white matter structures appeared to be normally developed ( Figures S2A and S2C). In contrast to ErbB4 mutants ( Neddens and Buonanno, 2010), the number of GAD67-positive cells in the hippocampus ( Figures 3C and 3E) and their cortical-layer-specific distribution ( Figures 3D, 3F, and S2D) were not altered in Emx?Nrg1f/f mutants at postnatal day (P) 14. Whole-cell patch-clamp recordings of CA1 pyramidal neurons?revealed changes in neurotransmission Cefaloridine in 3-month-old Emx?Nrg1f/f mutants similar to findings in CK?Nrg1f/f mutants. The amplitude of sEPSCs was depressed ( Figures 3G�C3I), whereas both sIPSC amplitude and frequency (???p?selleck compound ( Figures 3P�C3R). These findings argue against an essential role for glial and projection neuron-derived NRG1 during interneuron migration and the formation of inhibitory cortical circuits but support NRG1 functions in the fine tuning of excitatory and inhibitory neurotransmission in projection neurons. CRD-NRG1 is the most prominent NRG1 variant in the mature cortex (Liu et?al., 2011). To test the hypothesis that CRD-NRG1 serves as a signal for ErbB-receptor-mediated synaptic tuning, we examined transgenic mice (Nrg1-tg) that express CRD-NRG1 from the neuronal Thy1.2 promoter ( Michailov et?al., 2004). Transgene expression was initiated around E16 ( Figure?S2B) and prominent in neocortex and hippocampus of the adult brain ( Figures 4A and 4B). CRD-NRG1 accumulated on the surface of projection neurons but was absent from interneurons, astrocytes, and oligodendrocytes ( Figure?4C). Western blot analysis revealed increased steady-state levels of phosphorylated ErbB4 receptor in the hippocampus of Nrg1-tg mice at 4 months of age ( Figure?4D).