New study reveals how repeated early-life seizures alter microanatomy of neurons
Rajalaxmi Natarajan, PhD
A recent study published in eNeuro from the laboratory of Dr. John Swann, director of the Gordon and Mary Cain Pediatric Neurology Research Foundation Laboratories at Texas Children’s Hospital shows how frequent seizures alter the microanatomy of neurons in the brain and that the activity of a specific enzyme may contribute to the cognitive and behavioral deficits observed in children with epileptic encephalopathies.
Epileptic encephalopathies are neurological disorders of early childhood characterized by frequent seizures, which cannot be controlled by commonly available anti-epileptic medications. Patients with these syndromes have neurobehavioral issues such as impaired cognition, intellectual disabilities and autism. It is thought that recurring seizures impair growth and function of neurons during a very crucial period of brain development.
Although these seizure-induced delays in learning and memory and other neurobehavioral symptoms have been recapitulated in many animal models, there is little understanding of the cellular and molecular steps that lead up to them.
Neurons, the fundamental units of nervous system, typically consist of a central cell body (soma), a long axon and many shorter processes known as dendrites that communicate messages from neighboring neurons to the cell body. Previous studies from the Swann lab have shown that frequent seizures suppress the growth of dendrites along with presence of excess calcium within neurons.
Calcineurin is a critical enzyme of the calcium signaling pathway and is highly expressed in neurons. It has an important role in regulating how neurons respond to alterations in network activity and intracellular calcium levels and also regulates long-term learning and memory.
In this study, researchers in the Swann laboratory used genetic techniques to specifically eliminate calcineurin from pyramidal neurons, primary excitatory neurons of hippocampus, a region of the mammalian brain responsible for memory and emotions. Long-term seizures were induced in brain slice cultures from these transgenic mice and after a few days, the brain slices were analyzed to test the effect of recurrent seizures on growth and branching complexity of dendrites.
Brain slices from wild-type mice showed significantly smaller dendrites and less complex branching patterns whereas animals in which calcineurin gene had been deleted did not show a significant changes in dendrites. This suggests that seizure- induced changes in dendrite morphology occur due to the calcineurin present in hippocampal pyramidal neurons.
Thus, this study suggests that modulation of calcineurin, in particular and calcium signaling, in general, would be a viable strategy to develop therapies for patients with frequent recurring seizures and intellectual and/or behavioral disabilities.