# Identifying cortical circuit changes in Akap11 mutant mice

> **NIH NIH R21** · BROAD INSTITUTE, INC. · 2022 · $195,000

## Abstract

Project Summary/Abstract
A major barrier towards developing effective therapeutics for psychiatric diseases like schizophrenia (SCZ) and
bipolar disorder (BD) is the lack of a clear underlying neurobiological mechanism. Multiple lines of evidence
from human studies and post-mortem tissue implicate changes to the cortical circuit, including cell-type
composition and local and long-range synaptic connectivity. However, this hypothesis has been difficult to test
directly due to a lack of tools to carry out systematic and unbiased analyses of cortical circuitry a lack of strong
genetic risk factors that can be modeled in mice and. In this proposal, we will develop standardized methods to
measure the cortical circuit using spatial transcriptomics combined with viral synaptic tracing. We will apply this
method to genes identified by recent, large-scale exome sequencing studies that have identified rare loss-of-
function mutations strongly associated with disease. Among those genes implicated in both BD and SCZ is
Akap11, whose gene product regulates PKA, a central signaling molecule that controls neuronal transcription
and plasticity, and GSK3β, the proposed target of lithium treatment in BD. We will use multiplexed error-robust
fluorescent in situ hybridization (merFISH) to classify the transcriptional identity of cortical cells and their
laminar distribution and how they are altered in Akap11 mutant mice (Aim 1). We will also optimize conditions
for both long-range and local synaptic tracing using replication-defective rabies viruses to explore alterations to
synaptic connectivity in Akap11 mutant mice (Aim 2). Local labeling of synaptic inputs with rabies will be
combined with merFISH-based to identify cell-type specific changes in connectivity. These experiments will
identify changes in cellular composition and connectivity caused by loss of Akap11 and generate hypotheses
on the circuit mechanisms underlying disease. Importantly, this proposal will also establish an analysis pipeline
for characterizing the cortical circuit that can be applied across many disease-associated variants. Future
studies using this pipeline will identify convergent circuit mechanisms across high-confidence risk factors that
are most likely to cause disease and provide promising targets for new therapies.

## Key facts

- **NIH application ID:** 10430545
- **Project number:** 1R21MH129560-01
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Adam Granger
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,000
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430545

## Citation

> US National Institutes of Health, RePORTER application 10430545, Identifying cortical circuit changes in Akap11 mutant mice (1R21MH129560-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10430545. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*