# The Role of Neuronal HLA Class Is in Developmental Plasticity

> **NIH NIH F30** · STANFORD UNIVERSITY · 2020 · $39,540

## Abstract

Project Abstract
 The many complex behaviors that the human nervous system must perform rely on the existence of
precise structural connections between neurons. During neural development, these precise connections are
established by an initial period of axon growth and indiscriminant synapse formation, followed by a later period
of activity-dependent synapse refinement, resulting in the formation of the mature circuit. Activity-dependent
synapse refinement is therefore essential for the development of a healthy brain. Furthermore, abnormalities in
these processes are implicated in the pathophysiological mechanisms of neurodevelopmental diseases.
 Work from the Shatz lab over the last several decades has sought to understand the molecular cues
that link changes in neural activity to changes in synapses and circuits. This research uncovered a surprising
role for the major histocompatibility class I (MHCI) molecules as important proteins in activity-dependent
synaptic refinement. This was surprising because the MHCI molecules were best known for their role in the
immune system, where they assist in defense against viruses and intracellular abnormalities. Research from
the Shatz lab and others has revealed that in neurons, MHCI molecules are regulated by neuronal activity, and
are required for the synapse elimination process that refines initial connections in the developing visual system
into the full adult circuit. In addition, large-scale genome-wide association studies have identified
polymorphisms in the MHCIs locus as strongly associated with several neuropsychiatric disorders, particularly
schizophrenia. Post-mortem studies reveal that schizophrenic patients have fewer synapses than controls in
some brain regions, further suggesting that schizophrenia may be a disorder of excess synapse elimination.
 However, until now, the bulk of the work linking MHCI and activity-dependent synapse elimination has
been confined to model organisms. The role of human MHCIs in activity-dependent plasticity and synapse
elimination has not previously been studied, and this represents a vital step forward in translating these
discoveries further into a clinical context. The central goal of this proposal is to use histological,
biochemical, electrophysiological, and genetic tools to determine the role of human MHCI molecules in
activity-dependent synapse refinement. Here, I present preliminary work that establishes human brain
organoids, 3D neuronal structures derived from induced pluripotent stem cells, as a feasible platform for
studying MHCI and activity-dependent synaptic changes in human neurons. I will utilize these organoids to test
the hypothesis that MHCI molecules can be found in human neurons, at synapses, where they function as
components of an activity-dependent synaptic refinement mechanism. In the long-term, this research will
provide a necessary link between previous mouse studies and human biology, opening the door for direct
study of the molecular...

## Key facts

- **NIH application ID:** 10053236
- **Project number:** 5F30MH120957-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Michelle Katherine Drews
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,540
- **Award type:** 5
- **Project period:** 2019-09-15 → 2021-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053236

## Citation

> US National Institutes of Health, RePORTER application 10053236, The Role of Neuronal HLA Class Is in Developmental Plasticity (5F30MH120957-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10053236. Licensed CC0.

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