# Regulation of striatal maturation by dopamine and macroautophagy: implications for neuropsychiatric disorders

> **NIH NIH F30** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $47,355

## Abstract

PROJECT SUMMARY
Neuropsychiatric diseases such as obsessive-compulsive disorder (OCD), schizophrenia and
autism affect 1-3% of the population and cause significant morbidity. Understanding the
underlying pathophysiology of these disorders would represent a significant step forward
towards developing novel therapeutics for these patients. Human imaging studies from patients
and animal models of OCD, autism and schizophrenia have linked dysfunction of the part of the
brain called the striatum to the symptoms of these diseases. The striatum is primarily composed
of medium-sized spiny neurons (MSNs) which maintain a hyperpolarized resting potential and
low firing rate. Before adolescence, MSNs, however, are hyperexcitable and transition
postnatally to their adult phenotype. Interestingly, in animal models of schizophrenia and
Parkinson's disease, in which dopamine is absent in the striatum, MSNs remain hyperexcitable
in adulthood. This suggests that the developmental acquisition of the adult MSN electrical
phenotype may be critical to striatal function in the adult and its failure to mature may lead to
neuropsychiatric diseases such as OCD, schizophrenia and autism. Nevertheless, little is known
about the mechanisms underlying the developmental transitions that occur in MSN electrical
properties.
Here, I propose to investigate the cell-extrinsic and intrinsic mechanisms that control maturation
of MSN excitability during adolescence. In Preliminary Data, I show that MSN excitability
dramatically decreases during adolescence as current through inwardly rectifying potassium
channels (Kir) increases. Remarkably, despite the increase in Kir current during adolescence,
Kir protein decreases. I show that in a mouse which lacks macorautophagy, a process used to
degrade synaptic receptors in the CNS, in MSNs, MSN excitability is not reduced during
adolescence and Kir protein levels fail to go down. In Aim 1, I propose to investigate the
mechanisms through which Kir proteins levels change during adolescence in the striatum,
whether this is regulated by macroautophagy and why increased Kir protein at young ages is
associated with reduced Kir currents. In Aim 2, I propose to investigate whether cell-extrinsic
cues, such as a dopamine, induce changes in MSN excitability during adolescence. The
proposal outlined here will use novel transgenic mouse models, electrophysiological and
biochemical techniques to address an important question in striatal physiology, with implications
for neuropsychiatric disease.

## Key facts

- **NIH application ID:** 9994396
- **Project number:** 5F30MH114390-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Ori J Lieberman
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,355
- **Award type:** 5
- **Project period:** 2017-09-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994396

## Citation

> US National Institutes of Health, RePORTER application 9994396, Regulation of striatal maturation by dopamine and macroautophagy: implications for neuropsychiatric disorders (5F30MH114390-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9994396. Licensed CC0.

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