# The role of the clustered protocadherins in neural circuit formation and implications for neurodevelopmental disorders

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $625,186

## Abstract

PROJECT SUMMARY
 Functional circuits between the approximately 80 billion human neurons connecting trillions of synapses in
the human brain must be established during development. Failure to organize proper neural circuits has been
linked to neurodevelopmental disorders such as autism and neuropsychiatric diseases. During development,
individual neurons extend highly branched neurites that innervate the surrounding territory with minimal
overlap. Moreover, some neuronal subtypes, such as serotonergic and dopaminergic neurons, must tile
throughout receptive fields in the brain to ensure that their neurites do not cross over or clump with sister or
neighboring neurites or other neurons of the same type. Proper wiring of these neuronal cell types is required
for the physiological distribution of serotonin and dopamine in the brain.
 In mammals, a family of highly diverse cell-surface homophilic proteins, the clustered protocadherins
(cPcdh), provides each neuron a unique cell-specific identity required for normal neural circuit assembly. The
protocadherin gene cluster encompasses three distinct gene clusters, designated ,  and and previous
studies from our laboratory demonstrated that a single gene in the Pcdh gene cluster (Pcdhc2) is required
for normal serotonergic wiring in mice. Deletion of the entire Pcdh gene cluster or Pcdhc2 alone led to
clumping and crossing of serotonergic neurons (a tiling defect), and altered behavior (depression and
enhanced fear response).
 These findings provided significant advances in defining a role for individual cPCDH proteins in specific
neuronal subtypes; however, a role for the exclusive expression of specific cPcdh isoforms in other neuronal
subtypes and the mechanisms used to execute self-avoidance and tiling remain poorly understood. Here, we
propose to address these gaps in understanding by studying the role of the cPcdh gene cluster in the wiring of
dopaminergic neurons and behavior in mice. In Aim 1, we will survey the transcriptional landscape of cPcdh
isoforms across midbrain dopaminergic neurons in mice. In Aim 2, we will investigate the role of Pcdhβ cluster
on dopaminergic wiring, dopamine release and reward prediction and novelty behaviors. In Aim 3, we will
examine the mechanism by which PCDHβ proteins, establish proper DAN organization. Together, these new
directions should provide novel insights into the molecular logic underlying neural circuit formation and have
implications for neurodevelopmental and neuropsychiatric disorders.

## Key facts

- **NIH application ID:** 10873856
- **Project number:** 5R01MH108579-09
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** THOMAS P MANIATIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $625,186
- **Award type:** 5
- **Project period:** 2016-01-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873856

## Citation

> US National Institutes of Health, RePORTER application 10873856, The role of the clustered protocadherins in neural circuit formation and implications for neurodevelopmental disorders (5R01MH108579-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10873856. Licensed CC0.

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