Journal Club: Mouse model of Fragile X Syndrome show delayed maturation of synapses in the cochlea, as the potential cause of auditory hypersensitivity.

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Today's journal article

Chojnacka M, Skupien-Jaroszek A, Dziembowska M. Delayed structural maturation of inner hair cell ribbon synapses in a mouse model of fragile X syndrome. 

Why I picked this article

Fragile X Syndrome is a familial disease caused by a mutation in the FMR1 gene on chromosome X. Fragile X Syndrome is known for its effects on cognition and anxiety, but one of its lesser-discussed symptoms is auditory hypersensitivity. Auditory hypersensitivity is a heightened sensitivity to sound that causes discomfort or distress. Why such hypersensitivity is associated with Fragile X is not known. 

The cochlea is a sensory organ for hearing, and it contains sensory cells (= hair cells) that detect sounds, and auditory neurons (= spiral ganglion neurons). Sensory hair cells and spiral ganglion cells communicate via synapses, and spiral ganglion neurons propagate the signals to the brain. 

The researchers hypothesised that the hypersensitivity in Fragile X may come from changes during the development of auditory perception that happens in the brain. To investigate this, researchers focus here on ribbon synapses of the inner hair cells in the cochlea. These ribbon synapses are specialised structures that connect hair cells to the spiral ganglion neurons efficiently. The researchers explore whether the Fragile X mental retardation protein (FMRP), which is missing in the Fragile X Syndrome, plays a role in the maturation of these synaptic connections.

Some of the research findings

Animal model:

  • Fmr1 knockout mice (Fmr1 KO), which lack the FMRP protein, were used as the animal model for Fragile X Syndrome.
  • Background and control mice were FVB.129
  • Postnatal day 5, 14, 48, and 80-day-old (adult) mice were used. 
  • Lack of FMR1 protein in KO mice was confirmed by microscopy.

Findings: 

  • FMRP was found to be present in normal mouse cochleae, particularly within inner hair cells. This was absent in KO mice as expected. 
  • The team examined the development of ribbon synapses in the inner hair cells at early postnatal days (P5 and P14) by examining proteins found on the hair-cell side and the spiral ganglion neuron side of the synapse. 
  • The total number of synapses was the same throughout the developmental stage. 
  • However, the coupling of synapses was different, particularly during early development (~P14). 
  • In Fmr1 KO mice, ribbon synapses showed delayed maturation during these early developmental stages.
  • By adulthood (P48), the overall synaptic structure appeared normal, as confirmed by electron microscopy — meaning the delay was developmental, not permanent structural damage.
Taken together, there seems to be an impact on the synapse maturation process during the developmental period when synapses are refined, and the processing of sounds in the brain is fine-tuned in the Fragile X Syndrome mouse model. This could be the underlying pathology of hypersensitivity in human Fragile X syndrome. 
Part of Figure 3C. Control (left) and Fragile X Model (right), showing synapse proteins (red and green). 

Haruna's takeaway

The difference in the animal cochlea was very subtle, compared with the huge pathology in the cochlea that is obvious. It's the combination of high-quality microscopy data and quantification that has managed to identify this subtle change. It would be very interesting to continue working with this animal model to see what the consequences of such are in the auditory processing maturation in the brain. 

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This is Haruna's 47/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.