# Neural coordination and discoordination in Fmr1 null mice

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2021 · $343,384

## Abstract

ABSTRACT
Full mutation of the FMR1 gene causes loss of the fragile X mental retardation protein (FMRP) and fragile X
syndrome (FXS) characterized by intellectual disability with devastating cognitive consequences and features
of autism. Study of Fmr1 knockout (KO) mouse models of the FXS genetic defect identified that loss of FMRP
dysregulates translation at synapses, leading to synaptic dysfunction, for example excessive synaptic
depression in response to group 1 mGluR stimulation. Unfortunately, despite substantial knowledge of the
molecular consequences of FMR1 alteration, how the molecular changes lead to the clinical, cognitive
manifestations is unknown.
We consider a systems level analysis and use the hippocampus as a model cognitive system. We propose that
impaired cognition in Fmr1 KO mice is due to the inability of information-carrying hippocampus principal cell
spike trains to represent distinct streams of information because of the dysregulation of synaptic transmission.
As a result, cognitive deficits primarily manifest when FXS model mice are challenged to generate distinctive
neural representations in situations that are inconsistent with the information they have previously learned.
Preliminary findings from analysis of temporal coordination amongst hippocampal place cell spike trains, local
field potentials (LFPs), and conjoint action potential and LFP (spike-field) coordination provide substantial
evidence in support of the central “excitation-inhibition discoordination” hypothesis of this work. The hypothesis
asserts that cognitive deficits in FXS arise because dysregulated learning-induced changes of synaptic
network function cause discoordinated discharge within networks of excitatory and inhibitory neurons.
We test the hypothesis by comparing FXS model and control mice in a variety of memory discrimination tasks.
We will examine conventional Fmr1 KO mice in which the gene is mutated in all cells, as well as mice in which
the mutation is restricted to excitatory (Fmr1 KOe) or inhibitory (Fmr1 KOi) neurons to learn whether
dysfunction in one cell class is sufficient to cause cognitive dysfunction. We will also measure how memory
training changes synaptic function within the hippocampus circuit by recording evoked potentials across the
somatodendritic synaptic compartments of dorsal hippocampus in freely-behaving mice. Finally, we will
investigate abnormalities in how memory-related Fmr1 place cell ensemble discharge is controlled by
oscillations in the LFP that arise from inputs at distinctive dendritic compartments and causally test whether the
abnormality contributes to memory discrimination impairment using chemogenetic manipulations of the inputs.
These studies evaluate a novel, circuit-driven neuromodulatory therapeutic concept for reducing cognitive
disability in FXS and perhaps other disorders.

## Key facts

- **NIH application ID:** 10145083
- **Project number:** 5R01NS105472-05
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** ANDRE ANTONIO FENTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $343,384
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145083

## Citation

> US National Institutes of Health, RePORTER application 10145083, Neural coordination and discoordination in Fmr1 null mice (5R01NS105472-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145083. Licensed CC0.

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