# Neural function of the human memory-associated protein KIBRA: bridging molecular to circuit-level function

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $405,000

## Abstract

Understanding the biological basis of complex behavior is a major challenge in neuroscience, and
disorders of complex brain function exact an enormous social and financial burden. Solving this problem
requires understanding how information processing integrates across molecular, cellular, and circuit levels to
influence behavior, and how disease-associated risk factors impact such information processing. Numerous
studies demonstrate that common variants of KIBRA (enriched in KIdney and BRAin) associate with human
memory performance. KIBRA polymorphisms and gene expression also associate with disorders of complex
brain function including schizophrenia (SCZ) and autism spectrum disorder (ASD), and a strikingly large
proportion of neuronal KIBRA binding partners associate with SCZ, bipolar disorder, and/or ASD. Thus,
KIBRA represents an ideal candidate to reveal molecular mechanisms that control synaptic plasticity and
circuit function responsible for normal cognitive processes that are impaired in mental illness.
 We recently identified KIBRA (enriched in KIdney and BRAin) as a regulator of AMPAR trafficking, synaptic
plasticity, and learning and memory in rodents, but the mechanisms by which KIBRA influences these
processes and the impact on circuit dynamics remain unclear. This project aims to elucidate KIBRA function
across multiple levels of information processing via three aims: 1) identify molecular mechanisms by which
KIBRA protein complexes respond to neuronal activity and regulate AMPAR trafficking, 2) determine the
molecular and developmental requirements for KIBRA in bidirectional synaptic plasticity, and 3) establish the
role of KIBRA in regulating circuit dynamics. Intriguingly, despite robust expression of KIBRA in both the
juvenile and adult brain, deficits in synaptic plasticity do not emerge until young adulthood in constitutive
KIBRA knockout (KO) mice, a time course consistent with the onset of neurodevelopmental disorders such as
SCZ and BPD. Thus, our experiments will also evaluate developmental maturity as a factor impacting the
function of KIBRA protein complexes and the neural response to perturbation of KIBRA. To accomplish these
goals, we will use domain mutants to identify KIBRA interactors required for trafficking of endogenous
AMPARs, employ biochemical and advanced imaging methods (Fluorescence Fluctuation Spectroscopy) to
identify activity-regulated dynamics and stoichiometry of KIBRA complexes, examine functional and structural
synaptic plasticity in acute brain slices from constitutive and conditional KIBRA KO mice, and perform in vivo
electrophysiology in freely behaving mice to evaluate the role of KIBRA in behaviorally-driven circuit dynamics.
These proposed studies will reveal critical insight into the function of human-memory- and neurodevelopmental
disorder-associated KIBRA complexes at multiple levels of information processing, with broad implications for
understanding the mechanisms and neurodevelopmental vu...

## Key facts

- **NIH application ID:** 10151476
- **Project number:** 5R01MH117149-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** LENORA J VOLK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151476

## Citation

> US National Institutes of Health, RePORTER application 10151476, Neural function of the human memory-associated protein KIBRA: bridging molecular to circuit-level function (5R01MH117149-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10151476. Licensed CC0.

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