Altering Nerve Signals May Lead to Future Treatments in Children with a Severe Developmental Disorder

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In laboratory studies, a team of neurology researchers has unraveled cellular origins of a severe developmental disorder in children that causes epilepsy, intellectual disability and autistic-like symptoms. By analyzing how different types of neurons produce distinct abnormal symptoms in animals, the scientists found suggestions of potential treatments for children affected by the rare disease.

CDKL5 deficiency disorder (CDD) causes epilepsy (including early-onset seizures), intellectual disability and autistic features such as repetitive behaviors in affected children. It results from a mutation in the CDKL5 gene that disrupts neuronal signals in brain synapses. There are currently no drugs approved specifically for CDD.

The new findings, published June 14, 2019, in Nature Communications, reveal some of CDD’s complexity: in a mouse model, different types of nerve cells give rise to distinct symptoms. “This novel disease model suggests that drugs that target signals in specific sets of neurons might decrease autistic behaviors in humans without worsening the cognitive deficits in memory or learning seen in patients with CDD,” said study leader Douglas A. Coulter, PhD, a neurology researcher at Children’s Hospital of Philadelphia. Coulter co-led the study with Zhaolan Zhou, PhD, from the Department of Genetics of the Perelman School of Medicine at the University of Pennsylvania.

Coulter explained that CDD, like other neurological disorders, involves disruptions in the delicate balance between excitability and inhibition, through the actions of opposing neurotransmitters: glutamate and GABA. Blocking expression of the CDKL5 protein in glutamatergic neurons causes hyperexcitability, including seizures and autistic-like behaviors. In contrast, blocking CDKL5 expression in GABAergic neurons shifts the balance in the opposite direction, inhibiting nerve signals and impairing learning and memory.

Coulter, who has long studied neuronal circuitry, analyzed two types of laboratory mice to compare the effects of selectively “knocking out” CDKL5 protein expression in either type of neuron.

His study team found that mice lacking CDKL5 in glutamatergic neurons showed impaired learning and memory, resembling the intellectual disability seen in CDD patients. The mice did not show abnormalities in sociability, or in stereotypic or anxiety-related behaviors, implying that distinct cell-type processes operate in CDD-related autistic-like behaviors in mice.

In another group of mice lacking CDKL5 in GABAergic neurons, the researchers found autistic-like behaviors, but no impairments in learning or memory. The mice also had hyperactive synaptic activity and higher levels of NMDA receptors, which are key subtypes of glutamate receptors.  When the scientists used the dementia drug memantine to decrease NMDA receptor activity, they reduced the autistic-like behavior in the animals.

In an additional experiment, the study team created a novel mouse model that carried a human mutation found in CDD patients. Those mice had increased NMDA receptors, but as with the previous mouse model, blocking NDMA signaling decreased autistic-like behaviors. Overall, the research suggested that manipulating these interactions could someday treat autistic-like behaviors in humans.

Coulter cautioned that further studies of specific signaling pathways and neural circuitry is needed before targeted therapies can be developed for use in patients. He added, “This is a potentially promising avenue of research, and this knowledge of basic mechanisms might offer insights into other rare neurological disorders.”

Funding for this study came from the National Institutes of Health, the Loulou Foundation, the International Foundation for CDKL5 Research and other sources.

Learn more about the study.

Contact: The Children’s Hospital of Philadelphia,

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