Neurobehavioral deficits reported to originate independent of seizures in an animal model of childhood epileptic encephalopathy
Rajalaxmi Natarajan, PhD
Tue, 08/11/2015
Childhood epileptic encephalopathies (EEs) comprise a group of seizure disorders that manifest early in life and are commonly associated with abnormalities in cognitive, sensory and motor skills. There are various causes of childhood EEs. Injury to the brain during development of the fetus or at birth is a common cause. Thanks to recent advances in exome sequencing technology, it is increasingly evident that many rare EEs are a result of sporadic mutations in individual genes.
Recently, eight patients with Lennox-Gastaut syndrome and Infantile Spasms were documented to carry spontaneous mutations in dynamin 1 (DNM1). As the efficacy and affordability of genetic diagnostic tests for EEs improves, we can expect to identify more patients carrying DNM1 mutations. Just like children with infantile spasms, those with DNM1 mutations grow up to have other types of epilepsy, global developmental delay, and intellectual disabilities that do not respond to current treatments.
Dynamin 1 is a large molecule important for generating energy and mechanical force required for the release of neurotransmitters. These neurochemicals serve as messengers between nerve cells. Some neurotransmitters are inhibitory and dampened nerve activity while others are excitatory and augment activity. While the exact mechanism by which loss of DNM1 function leads to seizures and cognitive delays is not known, it is suspected that an impaired release of inhibitory neurotransmitters due to DNM1 mutations may cause seizures.
In clinical and experimental epilepsy research, it has been observed that severe and frequent seizures alter normal nerve cell development and it is believed that this leads to behavioral deficits. Based on this paradigm, it is thought that DNM1 mutations produce epilepsy and these recurring seizures produce neurobehavioral problems.
Interestingly, contrary to most DNM1 patients who begin to have seizures very early in infancy, two patients were found to exhibit developmental delays without ever having a seizure. Similar observations have been recently made for other EE genetic syndromes. This provides a clue that certain DNM1 variants may have independent effects on seizure activity and neurobehavior.
A recent paper1 published in PLoS Genetics by Asinof et al., provides experimental evidence that neurobehavioral defects in DNM1-associated EEs can occur independent of seizures.
In the past, homozygous “fitful” mice carrying a specific type of mutation in Dnm1 gene have been used as genetic models of DNM1 EE because they displayed many the features of the childhood syndrome. To test if the development of neurobehavioral defects depends on seizures in this EE, the authors of this study used genetic manipulations to generate a series of “conditional” mouse strains in which DNM1 were eliminated from only certain types of neurons in the brain.
The investigators report that removal of Dnm1 from different types of inhibitory neurons in the brain produced seizures of varying severity without any obvious signs of other neurobehavioral issues. Interestingly, elimination of Dnm1 gene from excitatory neurons was not sufficient to cause severe early-life seizures but did cause hyperactivity, repetitive and depressive behaviors and anxiety.
Thus, the authors conclude that in DNM1 mutant mice, seizures and neurobehavioral abnormalities have independent neuronal origins.
Clinical implication of this study for patients suffering from Dnm1-associated EEs is that early treatment of seizures alone may not be sufficient to halt cognitive and other neurobehavioral defects. For such patients, a combination of drugs that prevent seizures and neurobehavioral defects may be needed. Moreover, this study also suggests that a similar separation of effects may also exist in other genetic forms of EEs and this will need to be explored in the future.
Reference:
Asinof et al., Independent Neuronal Origin of Seizures and Behaviroal Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy. PLoS Genetics. 2015 Jun 30; 11(6):e1005347.
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