How Do Specific Sets of Neurons Influence Autistic-like Features of CDKL5 Deficiency Disorder?

Aug 13 2019

How Do Specific Sets of Neurons Influence Autistic-like Features of CDKL5 Deficiency Disorder?

The findings:

Researchers studying CDKL5 deficiency disorder (CDD), a complex and severe neurodevelopmental condition caused by mutations in the CDKL5 gene, gained novel insights into CDD’s underlying mechanisms. Their findings suggest that disrupted early development of neural circuitry has downstream consequences, disturbing neurotransmitter pathways and resulting in cognitive problems and autistic-like behaviors.

Previous research by the scientific team demonstrated that loss of CDKL5, which provides instructions for making a synaptic protein essential for normal brain development and functions, in forebrain glutamatergic neurons is implicated in learning and memory deficits. Their new findings suggest that loss of CDKL5 in forebrain GABAergic neurons leads to autistic-like features in mouse models of CDD.

Taken together, the study team’s results point to distinct cellular origins for the intellectual and behavioral impairments in CDD.

Why it matters:

Other rare pediatric neurodevelopmental conditions like CDD may exhibit a similar constellation of symptoms that could result from an imbalance of excitatory (glutamate) and inhibitory (GABA) neurotransmitters in the brain. When activity in developing neurons is skewed toward excitation, autistic-like behavioral phenotypes tend to appear; when activity is skewed toward inhibition, cognitive problems arise. Now that researchers know contrasting patterns of circuit dysfunction and NMDAR signaling underlie some features of CDD, they can explore new therapeutic avenues to treat the related symptoms.

Who conducted the study:

Study leaders Douglas Coulter, PhD, a neurology researcher at Children’s Hospital of Philadelphia, and Zhaolan Zhou, PhD, from the Department of Genetics of the Perelman School of Medicine at the University of Pennsylvania, collaborated on the project with their lab staffs and with lead authors Sheng Tang and Barbara Terzic, who are graduate students at Penn.

How they did it:

The researchers analyzed CDKL5-deficient mouse models that exhibited behavioral phenotypes similar to how CDD manifests in humans. Selectively knocking out CDLK5 from specific sets of GABAergic interneurons allowed the study team to discriminate where CDD behavioral phenotypes could be originating. They paired these results with findings from a previous study, where they had knocked out CDLK5 in glutamatergic excitatory cells.

Many of the CDD phenotypes segregated in these two conditional knockout strategies. The memory and learning phenotypes were mimicked by knocking out CDLK5 in glutamatergic cells. The autistic-like phenotypes occurred with the GABAergic knockouts, coupled with elevated levels of NMDA receptors.

Based on these findings, the study team began preliminary investigation of therapeutic opportunities for CDD. Currently, no drugs are approved specifically for CDD. When the researchers applied low concentrations of NMDA antagonists — using the dementia drug memantine to block the hyperexpression — they reduced autistic-like behaviors observed in the mouse models. The researchers have not yet explored therapeutic avenues for the learning and memory problems possibly related to over inhibition of NMDA receptors.

Quick thoughts:

“When we started discriminating between the knockouts’ effects on certain populations of neurons, all the behavioral phenotypes segregated,” Dr. Coulter said. “They went completely into two different camps. When you put this deletion in excitatory cells, you disrupted learning and memory. And when you put it into inhibitory cells, you disrupted normal social behaviors. This conditional deletion strategy has been amazing in terms of the leverage it has given us to figure out this complex disorder.”

What’s next:

Dr. Coulter cautioned that additional studies of specific signaling pathways and neural circuitry is needed before targeted therapies can be developed for use in patients with CDD. The study team will continue its preclinical investigation to look into the role of CDKL5 in sub-populations of interneurons. Further clarity on some of the fundamental mechanisms and early development disruptions in the nervous system may hold broader implications for other neurodevelopmental conditions. The study team’s work brings into sharper focus the conditional knockout strategy as an informative way to explore commonalities in rare disease phenotypes. The CHOP and Penn teams continue to analyze the neural circuitry that could be involved with an epilepsy phenotype that also appears in CDD as early-onset seizures in infancy.

Where the study was published:

The study appeared in Nature Communications.

Where to learn more:

Find out more about Dr. Coulter’s lab and Dr. Zhou’s lab. Also see this CHOP News article.