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Developmental biology - Brain Seizures

When an autistic brain can't calm down

Mutation linked to first time seizures in autism may become a new drug target...


Autism spectrum disorder is a highly prevalent neurodevelopmental disorder - affecting one in 68 children - characterized by a range of symptoms, including difficulty with communication and social interactions.

People with autism also often have other neurodevelopmental disorders and comorbidities, such as intellectual disabilities, seizure disorders or epilepsy, anxiety and depression.

One third of children who have autism spectrum disorder also have epilepsy related to a major autism risk gene, which can be mutated in patients with autism, CNTNAP2. But science couldn't explain why it causes seizures.
Now Northwestern Medicine scientists have discovered that a protein mutation on CNTNAP2 acts like a bad gardener. It shrinks neurons' tiny branches and leaves - known as dendrite arbors and synapses - whose normal "leafy" density enables brain cells to relay messages in a controlled manner. Shrunken neural "folliage" causes a breakdown in message delivery.

An important function lost is Calm Down

In people with the CNTNAP2 mutation, inhibitory neurons - whose job is to maintain tranquility by calming excitatory neurons - don't grow enough branches and leaves. They lose the calming effect, which leads to seizures.

Of interest is that CNTNAP2 or "catnap2", works in tandem with another mutated gene, CASK which is implicated in mental retardation. Scientists now have a new target for drugs to treat both disorders. Peter Penzes PhD, Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences, and Director of the new Center for Autism and Neurodevelopment at Northwestern University Feinberg School of Medicine, published a new paper on the topic April 2 in Molecular Psychiatry.
"Now we can start testing drugs to treat seizures as well as other problems in autism. Patients with the mutation also have language delay and intellectual disability. So a drug targeting the mutation could have multiple benefits."

Peter Penzes PhD, is the Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences at Northwestern University Feinberg School of Medicine; and Director, the new Center for Autism and Neurodevelopment, Northwestern University Feinberg School of Medicine and lead author on the paper.

Catnap2 is an adhesive molecule that helps cells stick together, in this case helping synapses adhere to dendrites. But, it is a difficult molecule to target with drugs, Penzes explains.
But Catnap2's partner, CASK, is a social butterfly enzyme that interacts with many molecules. It can more easily be inhibited or activated with drugs. Penzes's team will screen drugs to activate Catnap2 as it appears to maintain healthy dendrite branches. When scientists blocked CASK in the study, dendrites didn't grow.

Next, Penzes will conduct high-throughput molecular screening to identify and possibly reverse some molecular abnormalities observed in autism.

Abstract
Contactin associated protein-like 2 (CNTNAP2) has emerged as a prominent susceptibility gene implicated in multiple complex neurodevelopmental disorders, including autism spectrum disorders (ASD), intellectual disability (ID), and schizophrenia (SCZ). The presence of seizure comorbidity in many of these cases, as well as inhibitory neuron dysfunction in Cntnap2 knockout (KO) mice, suggests CNTNAP2 may be crucial for proper inhibitory network function. However, underlying cellular mechanisms are unclear. Here we show that cultured Cntnap2 KO mouse neurons exhibit an inhibitory neuron-specific simplification of the dendritic tree. These alterations can be replicated by acute knockdown of CNTNAP2 in mature wild-type (WT) neurons and are caused by faulty dendrite stabilization rather than outgrowth. Using structured illumination microscopy (SIM) and stimulated-emission depletion microscopy (STED), two super-resolution imaging techniques, we uncovered relationships between nanoscale CNTNAP2 protein localization and dendrite arborization patterns. Employing yeast two-hybrid screening, biochemical analysis, in situ proximity ligation assay (PLA), SIM, and phenotype rescue, we show that these effects are mediated at the membrane by the interaction of CNTNAP2s C-terminus with calcium/calmodulin-dependent serine protein kinase (CASK), another ASD/ID risk gene. Finally, we show that adult Cntnap2 KO mice have reduced interneuron dendritic length and branching in particular cortical regions, as well as decreased CASK levels in the cortical membrane fraction. Taken together, our data reveal an interneuron-specific mechanism for dendrite stabilization that may provide a cellular mechanism for inhibitory circuit dysfunction in CNTNAP2-related disorders.

Authors: Ruoqi Gao, Nicolas H. Piguel, Alexandria E. Melendez-Zaidi, Maria Dolores Martin-de-Saavedra, Sehyoun Yoon, Marc P. Forrest, Kristoffer Myczek, Gefei Zhang, Theron A. Russell, John G. Csernansky, D. James Surmeier and Peter Penzes


Funding:
The study was supported by grants NS100785, MH097216 and F30MH096457 from the National Institute of Mental Health of the National Institutes of Health.

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Apr 11, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




One-third of children who have autism spectrum disorder also have epilepsy related to a major autism risk gene catnap2 which causes seizures. Image credit: CC0 Public Domain


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