Summary: Activating neurons in the medial prefrontal cortex can reverse breathing and memory abnormalities in mouse models of Rett syndrome, researchers report.

Source: Case Western Reserve.

It is a parent’s nightmare: a child is born apparently healthy, then stops meeting developmental milestones at one year old. Her verbal and motor skills vanish, and irregular breathing, seizures, and a host of other problems appear. The cause is Rett syndrome–a devastating genetic, neurologic disorder that typically affects girls, resulting in severe disability and often accompanied by autistic behavior. Most Rett patients will live into middle age and require specialized full-time care. There is no cure, but researchers from Case Western Reserve University School of Medicine have been working to find ways to restore brain function and reverse disabilities associated with Rett syndrome.

In a recent study, researchers identified a specific brain region–the medial prefrontal cortex–as being particularly important for some of the respiratory and cognitive abnormalities seen in Rett syndrome. The study used a Rett mouse model to show activating neurons in this region can reverse breathing and memory abnormalities in symptomatic animals.

The team studied mice harboring a defect in the gene that causes Rett syndrome in humans. In the mouse model, they found neurons in the medial prefrontal cortex are relatively inactive, because they lack adequate stimulation from other nerve cells. The researchers hypothesized that low activity levels in these neurons could be causing Rett symptoms. By using molecular manipulations, the researchers specifically activated the “sleeping” neurons. The procedure restored normal breathing in the mice and reversed a specific deficit in long-term memory.

“‘Waking up’ these neurons, or increasing their electrical activity, results in a reversal of disease symptoms. With respect to the behaviors we studied, we can literally switch the animals from the disease state to the normal state (and back) by waking up (or not) these neurons,” explained study lead David M. Katz, PhD, professor of neurosciences and psychiatry at Case Western Reserve University School of Medicine. “Thus, despite the severity of Rett syndrome, brain circuits in affected animals are sufficiently intact that, with appropriate manipulation, their functionality can be rescued and normal behavior restored.” The results are part of the PhD thesis research of James Howell, a graduate student in the Katz laboratory.

The findings suggest stimulating neurons in the medial prefrontal cortex might also be therapeutic for Rett patients. Researchers hope it could help normalize breathing and improve cognitive function. The same approach, applied to other brain regions, could potentially lead to other improvements, such as enhanced motor function.

Such therapies could also benefit other patients. According to the authors, Rett syndrome is one of the most physically debilitating disorders on the autism spectrum and is seen as a potential model for other types of autism. Said Katz, “Whatever we learn about what is wrong in the Rett brain, and how to treat this disorder, may be of benefit not only to Rett patients, but others on the spectrum as well.”

Katz is now working to specifically define the subsets of neurons in the Rett brain that need to be activated to reverse symptoms. “This will hopefully make it possible to design more precise therapeutic strategies,” Katz said. His team is also looking at ways to translate their mouse model findings into potential treatments for Rett patients.

About this neuroscience research article

Funding: Study funded by NIH/National Institute of Neurological Disorders and Stroke.

Source: Puja Bhattacharjee – Case Western Reserve
Publisher: Organized by
Image Source: image is in the public domain.
Original Research: Open access research in eNeuro.

Cite This Article

Case Western Reserve “Researchers Reverse Symptoms in Rett Syndrome Model.” NeuroscienceNews. NeuroscienceNews, 29 January 2018.

Case Western Reserve (2018, January 29). Researchers Reverse Symptoms in Rett Syndrome Model. NeuroscienceNews. Retrieved January 29, 2018 from

Case Western Reserve “Researchers Reverse Symptoms in Rett Syndrome Model.” (accessed January 29, 2018).


Activation of the Medial Prefrontal Cortex Reverses Cognitive and Respiratory Symptoms in a Mouse Model of Rett Syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2; Amir et al., 1999), a transcriptional regulatory protein (Klose et al., 2005). Mouse models of RTT (Mecp2 mutants) exhibit excitatory hypoconnectivity in the medial prefrontal cortex (mPFC; Sceniak et al., 2015), a region critical for functions that are abnormal in RTT patients, ranging from learning and memory to regulation of visceral homeostasis (Riga et al., 2014). The present study was designed to test the hypothesis that increasing the activity of mPFC pyramidal neurons in heterozygous female Mecp2 mutants (Hets) would ameliorate RTT-like symptoms, including deficits in respiratory control and long-term retrieval of auditory conditioned fear. Selective activation of mPFC pyramidal neurons in adult animals was achieved by bilateral infection with an AAV8 vector expressing excitatory hm3D(Gq) DREADD (Designer Receptors Exclusively Activated by Designer Drugs) (Armbruster et al., 2007) under the control of the CamKIIa promoter. DREADD activation in Mecp2 Hets completely restored long-term retrieval of auditory conditioned fear, eliminated respiratory apneas, and reduced respiratory frequency variability to wild-type (Wt) levels. Reversal of respiratory symptoms following mPFC activation was associated with normalization of Fos protein levels, a marker of neuronal activity, in a subset of brainstem respiratory neurons. Thus, despite reduced levels of MeCP2 and severe neurological deficits, mPFC circuits in Het mice are sufficiently intact to generate normal behavioral output when pyramidal cell activity is increased. These findings highlight the contribution of mPFC hypofunction to the pathophysiology of RTT and raise the possibility that selective activation of cortical regions such as the mPFC could provide therapeutic benefit to RTT patients.

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