# Injury of Hippocampal Interneurons following Neonatal Hypoxia-Ischemia and Therapeutic Hypothermia

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2020 · $199,800

## Abstract

PROJECT SUMMARY: With this project I will achieve my career goal of developing expertise in the field of
developmental neuroplasticity to apply new mechanistic approaches to target aspects of brain injury and
recovery not addressed by the current therapies in neonates. My rigorous mentorship, coursework and
research plans are aligned to address my specific knowledge gaps to ensure my career development as an
independently funded clinician-scientist within 5 years. To that end, the proposed experiments will provide the
opportunity to master methods of electrophysiology and advanced neuropathology. The research plan is based
on a strong scientific premise that hypoxia-ischemia (HI) brain injury after birth asphyxia persistently alters
mechanisms of synaptic plasticity in the neonatal brain and that therapeutic hypothermia (TH) does not fully
prevent these effects explaining the persistent memory disabilities documented in pre-clinical models and
human RCTs of TH. I hypothesize that delayed injury of inhibitory interneurons (INs) within the hippocampus,
the prime brain region involved in memory consolidation, leads to impairment of long-term depression (LTD),
an essential mechanism of synaptic plasticity. Disruption of ErbB4 expression and activation, crucial for
survival and maturation of INs, may provide the mechanistic link. The research hypothesis will be tested with
the following specific aims determining if: 1) the decreased number of hippocampal INs after neonatal HI alter
LTD; 2) the morphology and function of surviving hippocampal INs are altered at delayed stages after HI; and
3) disruption in ErbB4 activation leads to loss and/or maturational arrest of hippocampal INs at delayed stages
after HI. Here, I will use the Vannucci procedure to induce HI in p10 (full-term equivalent) C57BL6 and GAD67-
EGFP transgenic mice expressing a green fluorescent tag for INs. Mice will be randomized to receive
normothermia (36°C) or TH (31°C) for 4h. Synaptic activity will be evaluated using electrophysiology methods
paired to immunostaining and advanced neuropathology methods. Additionally, modulation of the ErbB4
system in-vivo will be induced using adeno-associated virus (AAV) transfection methods. The proposed project
is also highly innovative as it relates to: i) the subject of study, the neonatal brain; ii) the field of study, synaptic
plasticity after injury; iii) the methodology, the systematic pairing electrophysiology and immunostaining data,
and iv) the statistical plan, accounting for biological variables including sex. The results of this project and
future research derived from it will translate into novel neuron-specific therapeutic targets to attenuate memory
deficits after birth asphyxia. The project will be performed in a 5-year period addressing the aims sequentially.
The proposed experiments and timeline are within my capabilities and the capabilities of the laboratory, animal
care, and surgical facilities. Future research will include ...

## Key facts

- **NIH application ID:** 9935130
- **Project number:** 5K08NS096115-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Raul Chavez-Valdez
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,800
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935130

## Citation

> US National Institutes of Health, RePORTER application 9935130, Injury of Hippocampal Interneurons following Neonatal Hypoxia-Ischemia and Therapeutic Hypothermia (5K08NS096115-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9935130. Licensed CC0.

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