John W. Swann, Ph.D., Co-Director
Research focus: Basic mechanisms of the childhood epilepsies; the impact seizures have on normal brain development (with a focus on learning and memory); new animal models of infantile spasms; epilepsy associated with human focal cortical dyplasia; rational drug therapies
Dr. Swann's lab is devoted to understanding the neurobiological basis of epilepsies that are unique to infants and children. The catastrophic epilepsies of childhood occur during circumscribed periods of brain development; with maturation these seizure disorders disappear, only to be followed by different forms of epilepsy that are often unresponsive to any anticonvulsant medication. Children with these disorders are often cognitively impaired. Recently the Swann lab developed an animal model of infantile spasms, one of these catastrophic epilepsies. The animals have EEG abnormalities that are virtually identical to those seen in children, including the electrographic hallmark of this disorder, hypsarrhythmia. Studies are underway using a variety of in vivo and in vitro neurophysiological techniques to understand the basic mechanisms underlying these abnormalities. Our goal is to use this model to screen new therapies for this devastating neurological condition.
Cognitive deficits are also common in children who have intractable epilepsy. A number of confounding factors make it difficult to determine the cause of these impairments through clinical observation alone, but recurring seizures themselves have been thought to be contributing factors. The Swann lab has recently provided evidence for this hypothesis: infant mice who have experienced as few as 15 brief seizures are cognitively impaired as adult animals. Further studies using both in vitro slice culture models and in vivo models show that seizures alter the development of hippocampal pyramidal cells, suppressing dendrite growth in a way that appears to be dependent on NMDA receptor function. The lab is now deciphering the down-stream signaling pathways involved in growth suppression. At the same time, mice are being treated with NMDA receptor antagonists in an attempt not only to prevent seizure-induced growth suppression but also the learning and memory deficits produced by early-life seizures.
The Swann lab is also collaborating with researchers in the Cain Foundation Laboratories and a large number of clinicians at Texas Children's Hospital to discover the molecular mechanisms responsible for intractable epilepsy in children with cortical dyplasia. Studies of tissue removed during epilepsy surgery to cure children of this disorder suggest that abnormalities in the PI3 Kinase pathway are responsible for seizures in these children. Studies of animal models in Anne Anderson's Lab support this hypothesis. Indeed, drugs that suppress signaling through the PI3 Kinase pathway have been found to suppress seizures in animal models of cortical dysplasia. Currently, collaborations between NRI investigators of the Cain Labs and the epileptologists at Texas Children's Hospital are in the late planning stages for clinical trials to test the effectiveness of these drugs in children.
PTEN loss increases the connectivity of fast synaptic motifs and functional connectivity in a developing hippocampal network.
Barrows CM, McCabe MP, Chen H, Swann JW, Weston MC