Epilepsy is tied to up-regulation of specific proteins, which leads to an imbalance of excitatory and inhibitory synapses in the brain, according to University of New Mexico professor Wolfgang Müller, who delivered a seminar outlining his research on Friday at the Dartmouth-Hitchcock Medical Center. Müller’s work focuses on understanding the changes in neuronal plasticity that lead to seizures.
According to the Biomedical Research and Integrative NeuroImaging (BRaIN Imaging) Center web site, Müller received his MD-PhD in Germany before moving to the University of New Mexico in 2005 as a Director of Research at the Center. He studies neuronal plasticity in the hippocampal region, an area that is associated with Alzheimer’s disease and epilepsy.
The status epilepticus (SE) rats that he studies offer several interesting new clues into the etiological pathway of the disease. After two to three weeks, when the rats begin exhibiting seizure symptoms, they show an imbalance of excitatory glutamatergic synapses and inhibitory GABAergic synapses, which seem to be a crucial component of the epileptic phenotype. Specifically, neurons in the entorhinal cortex are overstimulated by the excess in glutamatergic synapses, causing seizures, Müller stated. According to an article by researchers at Center for Memory and Brain, Boston University, the entorhinal cortex is an important memory center that provides input to the hippocampus.
The source of the overstimulation is the up-regulation of the NKCC1 and down-regulation of the KCC2 co-transporter proteins. NKCC1 is a Cl- uptake co-transporter and KCC2 is a Cl- extrusion co-transporter. The excess of NKCC1 observed in SE rats altered Cl- ion concentrations and disturbed the excitatory and inhibitory balance in the brain. Müller showed that by restoring the Cl- concentration, he could undo the excitatory dominance and reduce or eliminate the seizures.
Müller used a NKCC1 blocker, called bumetanide, to counter the upregulation observed in SE rats. The technique was effective in restoring the normal Cl- concentrations and reducing seizures in the rats.
While Müller’s research offers an exciting new pathway for treatment, there are still questions to be answered. For example, what causes the NKCC1 upregulation in SE rats in the first place?
“This is quite a mystery,” Müller said. “It seems like there must be a more complex clock that after two to three weeks upregulates it.”
The nature of NKCC1 in epilepsy offers promising avenues for its cause and treatment.