# Convergent cellular and network mechanisms of ASD risk genes

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $117,163

## Abstract

ABSTRACT
A decade of gene discovery identified over 250 genes highly associated to autism spectrum disorder (ASD). One
of the next critical steps to better understand ASD etiology is to determine how ASD risk genes converge on
cellular and network function. One central locus at which ASD risk genes converge are prefrontal cortex (PFC)
layer 5 pyramidal neurons. Layer 5 pyramidal neurons have specialized dendritic arbors thought to function as
coincidence detectors to effectively integrate both local and long-range synaptic inputs. Abnormal dendritic
processing is suggested to contribute to social, cognitive, and communication deficits typically observed in ASD.
Our lab has recently identified dendritic impairments in mice haploinsufficient for Scn2a, which has some of the
strongest associated scores to ASD. Here, I will test the central hypothesis that multiple ASD risk genes with
distinct biological functions converge on impairments in dendritic excitability and synaptic integration. This work
is expected to reveal whether dendritic excitability is indeed a point of convergence across high-risk ASD genes
and will uncover precisely which aspects of dendritic excitability are most affected in these cases. In addition,
most ASD risk genes are known or predicted to cause ASD due to haploinsufficiency. I will also test whether cis-
regulation gene therapy could be a viable therapeutic approach to restore ASD risk gene haploinsufficiency and
downstream deficits in dendritic and synaptic functions. Our results will have a positive impact as this work will
reveal mechanisms that contribute to altered dendritic excitability, which, in turn, may give us greater insight to
the pathophysiology of ASD and may provide a novel therapeutic approach to restore convergent features of
neuronal and network dysfunction.

## Key facts

- **NIH application ID:** 10785523
- **Project number:** 1K99MH135209-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Andrew D Nelson
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $117,163
- **Award type:** 1
- **Project period:** 2023-12-05 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10785523

## Citation

> US National Institutes of Health, RePORTER application 10785523, Convergent cellular and network mechanisms of ASD risk genes (1K99MH135209-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10785523. Licensed CC0.

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