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.

Public Health Relevance

This project aims to understand the pathophysiology that causes the memory discrimination impairments seen in fragile X syndrome (FXS) the most common genetic form of intellectual disability and autism. We will determine whether learning-related synaptic dysfunction and consequent mental inflexibility of the hippocampus account for cognitive deficits in mutant mouse models of FXS, and whether pathway-specific neuromodulation can be therapeutic for the cognitive inflexibility of FXS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS105472-04
Application #
9903473
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mamounas, Laura
Project Start
2017-08-15
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
New York University
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Sacktor, Todd Charlton; Fenton, André Antonio (2018) What does LTP tell us about the roles of CaMKII and PKM? in memory? Mol Brain 11:77
O'Reilly, Kally C; Perica, Maria I; Fenton, André A (2018) Synaptic plasticity/dysplasticity, process memory and item memory in rodent models of mental dysfunction. Schizophr Res :