# Probing brain circuit and behavior with protein:protein interaction modulators

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2024 · $794,232

## Abstract

ABSTRACT
Psychiatric diseases are complex brain disorders associated with maladaptive plasticity of the brain circuit for
which we lack predictive preclinical measures of clinical efficacy. To fill this gap, we need to use molecular
knowledge to inform development of novel probes in order to interrogate the mechanisms that underlie circuit
deficits in these disorders and drive advanced therapeutic design. Protein-protein interactions (PPI) within ion
channel complexes fine-tune neuronal excitability and are emerging as links to the biology of psychiatric
disorders. Their highly specific and flexible interfaces make protein-channel interactions ideal targets for probe
development. Such molecular probes would provide the neuropharmacology community with optimal research
tools to parse out brain disease complexities and enable more effective drug design.
We have identified the PPI between the voltage-gated Na+ (Nav) Nav1.6 channel and its accessory regulator
protein, fibroblast growth factor 14 (FGF14) as a functionally relevant regulator of excitability of medium spiny
neurons (MSN) in the nucleus accumbens (NAc); a central component of the mesocorticolimbic circuit whose
dysfunction has been associated with a wide spectrum of neuropsychiatric disorders. Through a
bioluminescence-based high-throughput screen (HTS) and a round of chemical optimization we have identified
the new brain permeable probe 1028 that modulates FGF14:Nav1.6 channel complex formation and increases
Nav1.6 channel availability and MSN firing. When systemically administrated, 1028 increases accumbal
neuron firing and promotes hedonic states in situations lacking motivation, suggesting the compound can
modulate reward-related behaviors within the mesocorticolimbic circuit. Here, we are proposing to further
optimize 1028 for in vivo use by improving its potency and metabolic stability and determine its mechanism of
action at the molecular (Aim 1), cellular (Aim 2), circuital, and behavioral levels (Aim 3). Outcomes of this
proposed research will generate the first-in-class brain-permeant chemical probes to interrogate the reward
circuit, providing the foundation for pre-therapeutic development of a new class of PPI-based leads for a broad
spectrum of psychiatric disorders.

## Key facts

- **NIH application ID:** 10769793
- **Project number:** 5R01MH132226-02
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Fernanda Laezza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $794,232
- **Award type:** 5
- **Project period:** 2023-02-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769793

## Citation

> US National Institutes of Health, RePORTER application 10769793, Probing brain circuit and behavior with protein:protein interaction modulators (5R01MH132226-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10769793. Licensed CC0.

---

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