Deficit of PV+INs in the dorsal hippocampus after neonatal HI linked to recapitulation of immature ErbB4-expressing phenotype and upregulation of Nrg1 in the mouse.

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ESPR354
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Background: Neonatal hypoxia-ischemia (HI) reduces the number and dendritic complexity of parvalbumin (PV)+ interneurons (INs). Prior to PV expression, these INs are strongly ErbB4+ while migrating radially to the hippocampus. Nrg1, a neurotrophin produced by pyramidal cells, binds to post-synaptic ErbB4 to initiate the activity-dependent increase in the expression of PV and/or somatostatin (SST), Kv3.1b channels, and dendritic complexity. Satb1, a transcription factor, plays an important role in further maturation and maintenance. 

Objective: To test the hypothesis that an immature phenotype of MGE-derived INs persists in the dorsal hippocampus after HI and results in altered Nrg1 expression. 

Methods: C57BL6 mice were injured using the Vannucci model to produce cerebral HI at P10. HI mice were randomized to normothermia (NT, 36°C) or therapeutic hypothermia (TH, 31°C) for 4h and compared to anesthesia-exposed littermates. Mice were sacrificed at 24h, 5d, 8d, and 30d after injury to study: i) injury severity by GFAP IHC and cresyl violet staining, ii) protein levels of ErbB4 and Nrg1 in forebrain by western blot (WB), and iii) immaturity markers of MGE-derived INs, such as transcription factor Satb1 and receptor ErbB4. Additionally, MGE-derived IN maturity markers, PV and SST were studied in combination with immaturity markers and Nrg1 in the dorsal hippocampus using double/triple IF-IHC. 

Results: At P11, SSTINs were already abundant in the Oriens layer (Or) of the CA1 and CA3 with axonal processes extending towards the pyramidal cell layer to reach the Lacunosum-Moleculare layer (LM). Conversely, fewer PV-expressing INs were documented at P11 (CA3>CA1). By P15, the number of PV+ INs almost doubled and PV immunoreactivity (IR) continued to increase until P18. In most cases neonatal HI did not decrease the number of hippocampal SSTINs, except in the more severely injured hippocampi. HI persistently decreased the number of PV+ INs in the CA1 and CA3 (by P40). TH did not attenuate injury or deficit of PVINs in the dorsal hippocampus. HI decreased ErbB4 protein levels in forebrain at P18, but markedly increased Nrg1. However, specifically in the dorsal hippocampus at P18, the percent of PVINs expressing ErbB4 was greater in the CA1 and CA3 of both NT and TH injured mice compared to sham mice. Nrg1 IR was markedly increased in CA1 and CA3 at P18 and correlated with injury severity. The nuclear SAtb1+ IR was more common in SST+ than in PVINs at all time points in sham mice, although there was a significant proportion of INs that were PV positive. HI decreased the number of Satb1+ nuclei in the CA1 only at P11 (vs. sham).

Conclusion: In response to the deficit of mature PVINs and their axonal terminals targeting the soma of hippocampal pyramidal cells after neonatal HI, surviving PVINs may recapitulate an immature ErbB4-expressing phenotype. Pyramidal cells may release Nrg1 in an attempt to activate pathways mediated by ErbB4. 


Johns Hopkins University School of Medicine
Johns Hopkins University School of Medicine
Johns Hopkins University
Johns Hopkins University
Johns Hopkins University

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