Nature | Early training behavior before symptoms can reduce Rett syndrome

Written | Edited by Qi | Mutations in the xi X-linked gene MECP2 can cause Rett syndrome, a progressive neurological disease in which children will maintain normal development for one to two years before experiencing severe motor and cognitive decline.
So far, there is no effective treatment method.

Studies have reported that female mice lacking a Mecp2 allele can reproduce the key features of Rett syndrome.
Restoring Mecp2 gene expression in adult Rett mice can alleviate the disease, indicating that the nervous system is sufficiently intact to support recovery [1, 2 ].

Although gene therapy is an ideal treatment in principle, the sensitivity of the brain to the amount of MeCP2 protein poses a special challenge, because excessive protein load in turn can cause MeCP2 duplication syndrome [3].

In this case, it is particularly important to find a suitable alternative therapy.

Deep brain stimulation (DBS), a non-pharmacological method, can improve the learning and memory ability of Rett mice by stimulating low-activity hippocampal neural circuits [4].

So is it possible to imitate the effect of continuous stimulation while avoiding the invasiveness of DBS? Studies have suggested that behavioral training can improve the motor and cognitive abilities of children with autism [5].
Is this method also suitable for patients with Rett syndrome? Recently, the Huda Y.
Zoghbi team from the Children’s Hospital of Texas published an article titled "Presymptomatic training mitigates functional deficits in a mouse model of Rett syndrome" in Nature.
In this study, the author used Rett synthesis The Zheng mouse model found that intensive training started in the pre-symptomatic stage significantly improved the performance of specific motor and memory tasks, and significantly delayed the onset of Rett's symptoms.

The markers of neuronal activity and chemical genetic manipulation indicate that task-specific neurons that are repeatedly activated during training can produce more dendrites than untrained animals.

These results provide a theoretical basis for the necessity of genetic screening for Rett syndrome in newborns, because pre-symptomatic intervention may reduce symptoms or delay its onset.

Based on previous findings, the author wanted to know whether pre-symptomatic training in female Mecp2 heterozygous mice (hereinafter referred to as Rett mice) can enhance circuit activity and reduce behavioral defects.

Female Rett mice will show symptoms of dyskinesia at about 12 weeks of age.
In order to determine the effect of training before or after the symptoms appear, the authors observed the exercise performance of three groups of 24-week-old mice on the accelerating rotating rod device.
They are: A control group of wild-type and Rett mice undergoing spin-bar training (naive); an early training group (early training) that started training at the age of 8 weeks; and a late training group (late training) that received the same number of training but started at 22 weeks.

As expected, the performance of naive Rett mice was worse than that of naive WT mice.
The performance of the late training group was slightly better than that of the untrained Rett mice, while the performance of the early training group was significantly better than that of the untrained and late training groups (Figure 1 ). So can similar training improve the cognitive ability of Rett mice? By observing the performance of the three groups of mice in the Morris water maze, the author also found that the early training Rett mice performed better than the naive group and the late training group.

Figure 1.
Pre-symptomatic training can improve the motor coordination ability of Rett mice.
Because cortical and hippocampal dysfunction is the basis of learning and memory abnormalities in Rett mice, the author wants to know whether task-specific neurons in these areas exhibit pre-symptomatic training bands.
Coming change.

To this end, the author used cFos targeted recombination technology (FosTRAP) to label task-specific neurons activated in water maze training [6].

FosTRAP uses the gene-encoded cFosCreER to drive the expression of the Cre-dependent reporter gene (tdTomato).
Administering 4-hydroxy tamoxifen immediately after training ensures that only neurons activated during training are marked.

If the labeled neurons are task-specific, then after retesting the mice in the water maze, the cFOS in the tdTomato+ neurons will be reactivated.
As expected, there are more tdTomato+ in the retested mice in the water maze.
cFos+ neurons, indicating that task-specific neurons are involved.

To determine whether pre-symptomatic training requires task-specific neuron activity, the authors expressed design receptors specifically activated by design drugs (DREADDs) in task-specific neurons of trained mice, and used clozapine-N -Oxide (CNO) manipulates neural activity, that is, in the presence of CNO, neuronal activity is inhibited by the hM4Di DREADDs receptor, but stimulated by the hM3Dq DREADDs receptor.

If task-specific neurons are necessary for the benefits of presymptomatic training, then preventing their reactivation should damage spatial memory.

To this end, the authors injected AAV encoding hM4Di–mCherry or mCherry into wild-type and Rett mice that also express cFosCreER.
All groups started training at 4 weeks of age, and were in a water maze with CNO or control at 13 weeks of age.
Re-testing, neurons expressing mCherry express cFos, but neurons expressing hM4Di–mCherry do not, indicating that CNO prevents the reactivation of task-specific neurons, and CNO damages wild-type and Rett mice expressing hM4Di–mCherry Spatial memory (Figure 2).

Therefore, activating task-specific neurons is necessary to improve the pre-symptomatic training of Rett mice.
However, whether it is a sufficient condition is not yet known.

Figure 2.
Inhibition of task-specific neurons affects the beneficial effects of pre-symptomatic training in Rett mice.
For this reason, the authors further injected AAV encoding hM3Dq–mCherry or mCherry into wild-type and Rett mice expressing cFosCreER.

After the water maze training, CNO or control was given in the cage without additional retraining.

In the test session, the authors observed that CNO retained the spatial memory of wild-type and Rett mice expressing hM3Dq–mCherry, while the spatial memory of wild-type and Rett mice expressing mCherry and injected with CNO or hM3Dq–mCherry and injected control followed Decline over time.

Therefore, activating task-specific neurons is a necessary and sufficient condition for the benefit of training in Rett mice.

After confirming the involvement of task-specific neurons, the authors further compared the morphological and electrophysiological characteristics of the hippocampal CA1 neurons in the middle and late training of the water maze and the early training.

The results showed that pre-symptomatic training enhanced the dendritic complexity and spine density of MeCP2−CA1 neurons in Rett mice, and increased the spontaneous inhibitory postsynaptic currents (sIPSCs) and spontaneous excitability of MeCP2-neurons in Rett mice.
The frequency of postsynaptic currents (sEPSCs). Overall, this finding indicates that early training behavior before symptoms of Rett syndrome has practical significance in delaying the appearance of specific symptoms.

Although the genetic heterogeneity of neurodevelopmental disorders poses a major challenge to the development of treatments, the neural circuits that are the basis of the disease phenotype may be a common entry point for early training.

Pre-symptomatic diagnosis and early training are not only beneficial for patients with Rett syndrome, but also for patients with other neurological diseases.

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