# Mechanisms underlying cortical local circuit regulation by synaptic GEFs and GAPs

> **NIH NIH P50** · NORTHWESTERN UNIVERSITY · 2024 · $363,790

## Abstract

PROJECT SUMMARY
The thematic focus of this Center is to understand how a signaling hub of molecules that regulate small GTPases
contribute to the precise developmental formation and maturation of inter-connectivity between neuronal
components of cortical microcircuits. The Center will address this goal with interrelated projects that will provide
an in-depth examination of the function of Trio and SynGAP; two potent regulators of GTPase signaling in the
developing brain. Multiple signaling molecules are involved in the organization and refinement of cortical
microcircuits that are required for correct information processing in the cortex. Trio and Syngap1 are known to
regulate synaptic connections but how they contribute to precise arrangements of cortical microcircuits through
neuronal migration, synaptic morphogenesis and refinement of connections during development is not known.
Pathogenic variants in these genes are causally linked to neurodevelopmental disorders that, while characterized
by heterogeneous genetic etiology, have shared symptoms. Convergence in symptoms suggests that disorders
with diverse molecular causes can be understood by defining the pathophysiological consequences on the
synapses and circuits that underlie the disrupted behaviors. In Project 3, we will address the broader goals of
The Center by analyzing the roles of these complex signaling molecules in the formation and refinement of
cortical microcircuits. Using ex vivo functional electrophysiological and optogenetic mapping approaches we will
dissect the effect of disrupted Trio and SynGAP signaling on cortical architecture. The project will assess (1) the
spatial cell-type and temporal functions of Trio and SynGAP, (2) the importance of enzymatic and non-enzymatic
functional domains to their roles in cortical connectivity, and (3) the action of novel small molecule inhibitors of
these GTPase regulators in synaptic function and connectivity at acute and chronic timescales. These studies
will transform our understanding of how Trio and SynGAP function in developing cortical circuits and along with
collaborative and integrated efforts in the Center will create a foundational understanding of their roles in
neurodevelopment.

## Key facts

- **NIH application ID:** 10862387
- **Project number:** 1P50MH132775-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Anis Contractor
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $363,790
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862387

## Citation

> US National Institutes of Health, RePORTER application 10862387, Mechanisms underlying cortical local circuit regulation by synaptic GEFs and GAPs (1P50MH132775-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10862387. Licensed CC0.

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