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Updated: Jul 14, 2026
Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
Increased threshold for spike-timing-dependent plasticity is caused by unreliable calcium signaling in mice lacking
Rhiannon M Meredith1, Carl D Holmgren, Meredith Weidum
1Department of Experimental Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands.
Abstract:
Fragile X syndrome, caused by a mutation in the Fmr1 gene, is characterized by mental retardation. Several studies reported the absence of long-term potentiation (LTP) at neocortical synapses in Fmr1 knockout (FMR1-KO) mice, but underlying cellular mechanisms are unknown. We find that in the prefrontal cortex (PFC) of FMR1-KO mice, spike-timing-dependent LTP (tLTP) is not so much absent, but rather, the threshold for tLTP induction is increased. Calcium signaling in dendrites and spines is compromised. First, dendrites and spines more often fail to show calcium transients. Second, the activity of L-type calcium channels is absent in spines. tLTP could be restored by improving reliability and amplitude of calcium signaling by increasing neuronal activity. In FMR1-KO mice that were raised in enriched environments, tLTP was restored to WT levels. Our results show that mechanisms for synaptic plasticity are in place in the FMR1-KO mouse PFC, but require stronger neuronal activity to be triggered.
Insights
Fragile X syndrome impairs synaptic plasticity in mouse models. Increased neuronal activity or enriched environments can restore spike-timing-dependent long-term potentiation (tLTP) in the Fmr1 knockout mouse prefrontal cortex.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Fragile X syndrome, a genetic disorder caused by FMR1 gene mutations, is linked to intellectual disability.
- Previous research indicated a lack of long-term potentiation (LTP) at neocortical synapses in Fmr1 knockout (FMR1-KO) mice, but the cellular basis remained unclear.
Purpose of the Study:
- To investigate the cellular mechanisms underlying synaptic plasticity deficits in the prefrontal cortex (PFC) of FMR1-KO mice.
- To determine if spike-timing-dependent LTP (tLTP) is completely absent or altered in FMR1-KO mice.
Main Methods:
- Electrophysiological recordings in the PFC of FMR1-KO and wild-type (WT) mice.
- Analysis of calcium signaling in dendrites and spines.
- Assessment of tLTP following environmental enrichment in FMR1-KO mice.
Main Results:
- Spike-timing-dependent LTP (tLTP) induction threshold is elevated, not absent, in FMR1-KO mice PFC.
- Calcium signaling in dendrites and spines is compromised, with frequent failures in calcium transients and absent L-type calcium channel activity in spines.
- Restoring tLTP is possible by enhancing calcium signaling reliability and amplitude through increased neuronal activity.
- Enriched environments normalized tLTP in FMR1-KO mice to WT levels.
Conclusions:
- Synaptic plasticity mechanisms are present in the FMR1-KO mouse PFC.
- These mechanisms require heightened neuronal activity for induction, suggesting a threshold issue rather than a complete absence of plasticity.
- Environmental enrichment can rescue synaptic plasticity deficits in Fragile X syndrome models.
