Irregular Visual Perception in a Mouse Model of Fragile X Syndrome Could be Treated using Designer Therapies

Irregular Visual Perception in a Mouse Model of Fragile X Syndrome Could be Treated using Designer Therapies

Visual perception impairments in a mouse model of fragile X syndrome can be therapeutically targeted using designer therapies, according to a new study.

People with fragile X demonstrate similar visual impairments, suggesting that these specific therapies could be used to treat them.

The study, “Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible,” was published in Nature Neuroscience.

Atypical sensory processing — the abnormal processing of sensory stimuli — is observed in patients with fragile X and other forms of autism spectrum disorders (ASD).

In particular, several studies have shown that patients with fragile X have deficits in visual perception, which leads to irregular processing of visual information. This can negatively affect several aspects of patients’ lives.

A mouse model of fragile X, named Fmr1–/–, is a good model to study this issue as not only does it reproduce key aspects of the human disease, but also displays multiple neuropsychological symptoms such as anxiety, impaired cognitive flexibility, reduced social interaction, hyperarousal, and sensory over-reactivity.

A neural circuit refers to an interconnected population of neurons that carries out a specific function when activated. Neural circuits connect to one another to form large-scale brain networks.

Currently, progress in fragile X research is limited by a lack of clearly identifiable alterations in neuronal circuits that can explain why patients have complications in visual perception.

Therefore, researchers used this mouse model of fragile X to understand possible alterations at the level of neuronal circuits that may underlie atypical sensory processing associated with autism. Fragile X is ideally suited to address this issue because it is the leading inherited cause of autism.

Using a technique known as the go/no-go visual discrimination task, the team confirmed that Fmr1–/– mice displayed delayed learning of a visual discrimination task, indicating issues with visual perception. The go/no-go tasks are useful in the study of cognitive neurosciences, requiring animals to distinguish between two categories of stimuli.

Next, researchers looked at the mice’s primary visual cortex (V1), a part of the brain that processes visual information. Using a molecular technique called two-photon calcium imaging, researchers observed there were lower numbers of orientation-selective V1 cells.

Most V1 neurons are orientation selective, meaning that they respond strongly to lines, bars, or edges of a particular orientation (such as vertical) but not to the orthogonal orientation (such as horizontal). Orientation tuning is a measure of how much a cell signals depending on the orientation (straight, angled, horizontal) of a visual stimulus.

These orientation-selective V1 cells also had broader tuning (6.6° difference) between healthy and Fmr1–/– mice.

Hence, not only were there fewer orientation-selective V1 cells in fragile X mice,  but they also had orientation tuning impairments.

Researchers also found a reduction in the activity of parvalbumin (PV) interneurons — a type of neuron that coordinates certain dynamics required for memory consolidation — in the V1 region of fragile X mice compared to healthy ones.

As PV interneurons can play a major role in activating vital neuronal networks, researchers sought to reactivate these neurons by using designer receptors exclusively activated by designer drugs (DREADDs), that  targeted and activated PV cells in fragile X mice.

In fact, DREADDs could restore fragile X mice’s visual responses to those similar to healthy mice, which corresponded to an accelerated rate of learning.

“[O]ur study offers hope that simple therapeutic strategies targeting relevant but relatively subtle circuit defects may be of value in treating specific behavioral impairments in FXS [fragile X],” researchers concluded.

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