# Cellular Mechanisms of Convergence Among Autism Spectrum Disorder Genes

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $19,695

## Abstract

ABSTRACT
Recent progress in genetics has uncovered over 100 genes associated with autism spectrum disorder (ASD).
Identifying points of convergence among ASD candidate genes is the next critical step to translate gene
discoveries to pathophysiological changes in brain circuitry. One central locus at which ASD risk genes converge
are prefrontal cortex (PFC) layer 5 pyramidal neurons. These neurons have specialized dendritic arbors thought
to act as coincidence detectors between local inputs on their basal arbors and long-range modulatory inputs on
their apical tufts. Thus, pyramidal cell dendrites may be a major locus for synaptic integration. Abnormal dendritic
excitability is hypothesized to contribute to the social, cognitive, and communication deficits typically observed
in ASD, but how these deficits manifest at the cellular level remains unclear. Here, I propose that deficits in
dendritic integration and dendritic excitability are a core cellular phenotype of ASD. Specifically, I will test the
central hypothesis that impaired dendritic excitability is a point of convergence across multiple high-confidence
ASD risk genes. Our lab has recently identified dendritic impairments in mice haploinsufficient for a top ASD risk
gene, Scn2a. Scn2a encodes the voltage-gated sodium channel NaV1.2, which is critical for the backpropagation
of action potentials to apical dendrites to regulate synaptic integration, stability, and plasticity. Interestingly,
several high-risk ASD genes may interact with Scn2a—either through membrane scaffolding or gene
expression—in ways that could also result in impaired dendritic excitability. Ankyrins, for example, are a family
of scaffolding proteins known to localize sodium channels to the axon initial segment and nodes of Ranvier, sites
of action potential initiation and propagation. Here, we propose that ankyrin-B, the product of the ASD-associated
gene ANK2, is the primary ankyrin that localizes Nav1.2 in dendrites. Consistent with a loss of dendritic NaVs,
my preliminary data indicate that Ank2+/- and Scn2a+/- pyramidal cells have identical deficits in excitatory synapse
function. Upstream of this direct interaction, the ASD risk genes Fmr1 and Tbr1 have been shown to regulate
either Scn2a or AnkB expression. As a result, we expect dendritic excitability to be impaired when any of these
genes are affected. We will test our hypothesis by pursing three specific aims: Aim 1: To evaluate the effects of
Ank2 loss on dendritic sodium channel function and excitability. Aim 2: To investigate convergence of impaired
dendritic excitability in mouse models of ASD risk genes. Aim 3: To determine the effects of Scn2a
haploinsufficiency on basal versus apical dendritic excitability. This work is expected to reveal whether dendritic
excitability is indeed a point of convergence across high-risk ASD genes, and to further determine precisely what
aspects of dendritic excitability are most affected in these cases. Our results will hav...

## Key facts

- **NIH application ID:** 10687877
- **Project number:** 5F32MH125536-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Andrew D Nelson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $19,695
- **Award type:** 5
- **Project period:** 2021-09-30 → 2023-12-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10687877

## Citation

> US National Institutes of Health, RePORTER application 10687877, Cellular Mechanisms of Convergence Among Autism Spectrum Disorder Genes (5F32MH125536-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10687877. Licensed CC0.

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