Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder

Principal Investigator: SULZER, DAVID
Institution Receiving Award: COLUMBIA UNIVERSITY
Program: TSCRP
Proposal Number: TS110056
Award Number: W81XWH-12-1-0196
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $704,306.00


Tuberous sclerosis (TS) is caused by mutations in the TSC1 and TSC2 genes. TS research has examined the role of these mutations in making new proteins. Current research, however, has not explained a clinically very important issue: why the vast majority of TS patients present with epileptic seizures.

Our new evidence has uncovered evidence supporting a possible explanation for the development of seizure in this disease. The major non-neuronal cell in the brain is the astrocyte. These cells regulate synaptic function and development, as well as the clearance of brain metabolites, including toxic materials, and also express the mutant genes that cause TS; however, a role for them in TS neurological disorders has not been studied.

This proposal is designed to determine exactly which steps in normal development are due to the disease mutations in neurons or astrocytes. Our evidence so far indicates that a portion of the disease is due to a loss of the ability of the brain to normally remove synapses, which can lead to overstimulation and seizures. Some of this is apparently allied with effects on astrocyte function. In this proposal, we will first find the precise roles by using a culture system in which we compare the effects of TSC mutant and normal astrocytes on normal neurons. We will determine the normal synaptic removal ("pruning") occurs in the brain first in mouse models of TS, then which biochemical steps are involved and how they can be normalized by drug treatments, and finally using human autopsy tissue, if these same processes happen in patients with the genuine disease.

The experimental directions described may explain the cause of epilepsy, autism, and other neurodevelopmental common neurological features of TS: that normal synaptic pruning during the first years of life is inhibited via aberrant results with astroyctes. If these hypotheses are borne out, it will lend additional reason to explore drug treatments for TS during the period of normal synaptic pruning, i.e., early childhood when these symptoms first appear, and will encourage the exploration of therapies that target or circumvent the errors astrocyte regulation.

Direct replacement of existing astrocytes is not presently possible, but promoters that are highly specific for these cells are already well characterized. Thus, if our theory is supported, the field will be able to explore means to specifically target genes to astrocytes or astrocyte function rather than neurons during the period when TS is first diagnosed, which corresponds to the period of normal synaptic pruning. For example, astrocytes are responsible for glutamate reuptake by the protein GLT-1, and one of our experimental goals is to determine if this is affected by TSC mutation and if this underlies epilepsy. If it is, modulators of GLT-1 will provide a new clinical avenue for TS treatment.