Summary: Researchers report neurons in mice with a genetic defect that causes Fragile X are similar to those in mice without the syndrome, but fail to interact correctly. This failure results in the cognitive impairment associated with FXS.
Neurons in mice afflicted with the genetic defect that causes Fragile X syndrome (FXS) appear similar to those in healthy mice, but these neurons fail to interact normally, resulting in the long-known cognitive impairments, shows a new study by a team of neuroscientists.
The results point to a new approach to address FXS: targeting neuronal interactions rather than the immediate molecular abnormalities of genetic mutations.
“The genetic defect that causes the most widespread form of intellectual disability and autism is surprisingly characterized by normally functioning memory and cognition-encoding neurons,” explains André Fenton, a professor in New York University’s Center for Neural Science and the senior author of the paper, which appears in the journal Neuron. “But despite being individually normal, these neurons are abnormal in their interactions, which results in cognitive impairments.
“The good news, however, is we now have a better place to look for remedies: we can pursue a therapeutic strategy that targets neuronal interactions rather than the proximal molecular effects of a genetic mutation.”
The study also included Dino Dvorak, a post-doctoral fellow in NYU’s Center for Neural Science, Zoe Talbot, an NYU graduate student at the time of the study, Fraser Sparks, an NYU postdoctoral fellow at the time of the study and now at Columbia University, and researchers from SUNY Downstate Medical Center.
It’s long been known that FXS is caused by a mutation that shuts down a particular gene–FMR1–so the protein product it normally produces, FMRP, cannot be made. In their study, the scientists mimicked the genetic defect in FXS by mutating the FMR1 gene in mice so that it could not produce the protein FMRP, which is vital for learning and memory.
In a series of active place avoidance tests, the FXS mice could learn and remember a location they should avoid, but as expected, were unable to efficiently adapt to environmental changes that contradicted their prior experience; so, when the place to avoid was relocated, the FXS mice could not avoid the new location, unlike control mice that rapidly adapted to the new information.
When the researchers looked into what explained these cognitive flexibility deficits, they found that the neurons of the FXS mice appeared normal.
However, their examination also showed a lack of coordination among neurons–organized interaction that is crucial in processing information from contradictory sources. Specifically, the mutated FMR1 gene disrupted the functioning of the neurons in the hippocampus–a brain structure known to play a significant role in memory in general and for the place avoidance task in particular. The disruption prevented the neurons from appropriately forming and disbanding in groups–“neural coalitions” that work to perform cognitive tasks by transiently discharging together in time.
About this neuroscience research article
Funding: The research was supported, in part, by a grant from the National Institutes of Health (R01MH099128) and by a Simons Foundation Autism Research Initiative grant (SFARI 294388).
Source: James Devitt – NYU
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Normal CA1 Place Fields but Discoordinated Network Discharge in a Fmr1-Null Mouse Model of Fragile X Syndrome” by Zoe Nicole Talbot, Fraser Todd Sparks, Dino Dvorak, Bridget Mary Curran, Juan Marcos Alarcon, and André Antonio Fenton in Neuron. Published online January 18 2018 doi:10.1016/j.neuron.2017.12.043
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Normal CA1 Place Fields but Discoordinated Network Discharge in a Fmr1-Null Mouse Model of Fragile X Syndrome
•Excessive learning-induced CA3→CA1 synaptic transmission and plasticity in FXS mice
•Place fields of individual Fmr1-null CA1 place cells are normal in fixed conditions
•Unstable spike-field phase organization of Fmr1-null CA1 place cell discharge
•Ensemble place cell discharge is weakly coordinated in Fmr1-null mice
Silence of FMR1 causes loss of fragile X mental retardation protein (FMRP) and dysregulated translation at synapses, resulting in the intellectual disability and autistic symptoms of fragile X syndrome (FXS). Synaptic dysfunction hypotheses for how intellectual disabilities like cognitive inflexibility arise in FXS predict impaired neural coding in the absence of FMRP. We tested the prediction by comparing hippocampus place cells in wild-type and FXS-model mice. Experience-driven CA1 synaptic function and synaptic plasticity changes are excessive in Fmr1-null mice, but CA1 place fields are normal. However, Fmr1-null discharge relationships to local field potential oscillations are abnormally weak, stereotyped, and homogeneous; also, discharge coordination within Fmr1-null place cell networks is weaker and less reliable than wild-type. Rather than disruption of single-cell neural codes, these findings point to invariant tuning of single-cell responses and inadequate discharge coordination within neural ensembles as a pathophysiological basis of cognitive inflexibility in FXS.
“Normal CA1 Place Fields but Discoordinated Network Discharge in a Fmr1-Null Mouse Model of Fragile X Syndrome” by Zoe Nicole Talbot, Fraser Todd Sparks, Dino Dvorak, Bridget Mary Curran, Juan Marcos Alarcon, and André Antonio Fenton in Neuron. Published online January 18 2018 doi:10.1016/j.neuron.2017.12.043
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