About This Project

Ask the Scientists

What is the context of this research?

My research project is focused on understanding how hypothalamic hamartomas (HH) lead to the development of epilepsy in children. Fundamentally these growths or lesions are simply disorganized aggregates of neural tissue occurring deep within the brain yet they somehow develop seizure generating activity (i.e. they are epileptogenic). This epileptogenic activity then serves as an engine to drive epileptic seizure activity in higher brain centers. The resulting seizures are initially characterized by unprovoked laughter and are called gelastic seizures. While these early seizures appear to be comparatively harmless, they are poorly responsive to conventional drug therapy and gradually evolve into more serious seizures types, In addition to epileptic seizures, these children can develop several comorbidities including developmental delay,learning disabilities, autism. and precocious puberty. Ultimately, treatment usually involves surgical removal or destruction of the hamartoma. The hamartoma itself is composed of normal neuronal and glial (supporting) cells displaying a highly disorganized architecture and it is likely that this latter feature is responsible for its epileptogenic (seizure-inducing) nature. At present the cellular changes responsible for the development of epileptogenic activity in HH tissue remain unknown. The goal of my HH project is to determine whether the expression of specific components related to signaling between nerve cells (synaptic transmission) are responsible for HH epileptogenic activity. Since only frozen HH tissue is currently available (see section on research importance), I utilize cell membranes isolated from HH tissue and express these in a model system for pharmacological studies. This approach allows me to carry out "functional" studies of HH tissue that normally could only be accomplished with freshly resected tissue samples. With this unique system I propose to study both excitatory and inhibitory components of synaptic transmission. Using postmortem hypothalamus as our control tissue, I expect to be able to utilize pharmacological testing to discover changes in HH tissue that might be responsible for epileptogenic activity and thereby establish more specific targets from drug therapy.

What is the significance of this project?

Hypothalamic hamartomas (HH) are comparatively rare (1:200,000) but difficult to treat without surgery. From a research standpoint, these growths can provide unique insights into how normal neural tissue that grows in a disorganized manner can develop epileptic characteristics and go on to cause higher centers in the brain to also become epileptic. Better drug therapy can potentially be developed if we can understand why this disorganized neural tissue is able to cause seizures. This research also has implications for understanding epilepsy associated with other developmental defects such as cortical dysplasia. There are no animals models for HH and as such research is carried out using actual HH specimens removed at the time of surgery. These are becoming scarce as surgical treatment has evolved from tumor removal to tumor destruction with lasers. As such, the only material available to study HH is frozen tissue from previous surgeries. The Barrow Neurological Institute is a major referral center for HH surgery and as such we have a small repository of frozen HH tissue from previous surgeries. My work is uniquely suited to studying these tissues since I am able to isolate cellular membranes and study their interaction with neurotransmitters. We are the only lab in the US with this combination of methodology and tissue samples. By injecting neural membranes into frog eggs (oocytes), we utilize electrophysiological and pharmacological tools to determine how HH tissue differs from normal adjacent normal tissue. In this way we hope to gain insights into those changes which are responsible for seizure development.

What are the goals of the project?

The funds will maximize our current testing capacity and allow us to purchase specific pharmacological agents that we have not been able to afford thus far. Being that there is a limited amount of tissue available, it is imperative that any given sample be tested as exhaustively as possible. Adding a second computer-controlled delivery system will bring our testing capacity to maximum. The remaining funds will be used to purchase high grade oocytes that are necessary when injecting brain membranes.