# Mechanism of Lithium in Neurogenesis and Behavior

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2020 · $72,006

## Abstract

PROJECT SUMMARY
Bipolar disorder (BPD) is an affective disorder causing life-long cycling between mania and depression,
afflicting 1-2% of the population and resulting in suicide in 15% of patients. The etiology of BPD is unknown,
and first-line treatments such as lithium have no known mechanism of action. Our lab has shown that lithium
directly inhibits GSK-3, that lithium activates Wnt/β-catenin—a signaling pathway inhibited by Gsk3—in the
brain, and that GSK-3 inhibition mediates the behavioral effects of lithium in mice. This proposal combines
behavioral analysis with cutting-edge brain imaging techniques and modern mouse genetics to define with
cellular resolution the cells that are directly targeted by lithium in the brain, track cell fate decisions following
lithium-induced neurogenesis, and test the requirement for Gsk3, using conditional genetic deletion, in
mediating the behavioral and neurogenic effects of lithium. The first specific aim takes an unbiased approach
to identify which neurons and other cell types in the brain directly respond to lithium using a novel fluorescent
reporter for Wnt/β-catenin activity as a surrogate for GSK-3 inhibition. We will further identify the cell fate
decisions of adult hippocampal neural stem cells (NSCs) undergoing lithium-induced neurogenesis to
determine whether the pro-neurogenic effect of lithium is likely to play a direct role in its therapeutic
mechanism of action. The second specific aim asks whether Gsk3 loss specifically in postnatal forebrain
neurons is required to mimic lithium's effects on behavior, which was not tested in previous studies of GSK-3
inhibition on behavior. Furthermore, we will determine whether deletion of Gsk3 in specifically adult NSCs
phenocopies lithium's effects on adult hippocampal neurogenesis and NSC fate decisions. The research
strategy described in this proposal will provide the applicant, Dr. Melinda Snitow, comprehensive training in the
field of neurogenesis, mouse neurobehavioral testing, and state-of-the-art imaging techniques, which are
critical to develop a career studying the etiology and treatment of BPD. The proposed site of research, The
University of Pennsylvania's Perelman School of Medicine, provides comprehensive state-of-the-art physical
resources, combined with an extensive community of experts in neuroscience and behavior. The sponsor, Dr.
Peter S. Klein, is a leading expert on the molecular and behavioral effects of lithium and Gsk3. Dr. Klein's
extensive experience in the field of BPD research and pharmacology, and collaborations with neurogenesis
and behavior experts Dr. Amelia J. Eisch, Dr. Hongjun Song, and Dr. Elizabeth A. Heller, plus consultation
regarding clinical relevance with Dr. Chang-Gyu Hahn, will provide ideal training in behavioral neuroscience
and neuropsychopharmacology to prepare Dr. Snitow for a career in BPD research as an independent PI. The
proposed research will elucidate lithium's direct cellular targets that regulate b...

## Key facts

- **NIH application ID:** 9873101
- **Project number:** 5F32MH113334-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MELINDA SNITOW
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $72,006
- **Award type:** 5
- **Project period:** 2018-03-15 → 2022-03-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873101

## Citation

> US National Institutes of Health, RePORTER application 9873101, Mechanism of Lithium in Neurogenesis and Behavior (5F32MH113334-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873101. Licensed CC0.

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