UCSF

Structural abnormalities in the human brain, which result from disruption of cortical development, are often associated with neurological deficits such as mental retardation and epilepsy. Cortical malformations that result in epilepsy are often resistant to standard antiepileptic drugs leaving the patient with few options for successful treatment. A driving question in the field of epilepsy research is to understand the basis of seizure generation in the malformed brain, in the hope of providing new methods to treat this devastating condition. Lissencephaly in humans is characterized by a lack of cortical gyri and four-layered cortex, and by mental retardation and epilepsy. The Lis1 protein has been shown to interact with the dynein/dynactin complex and to be critical for neuronal migration. A mouse model of lissencephaly was created by heterozygous mutation of the Lis1 gene. The Lis1 +/- mutant mouse has neuronal disorganization of the cortex, olfactory bulb, and hippocampus. This mouse has been shown to have hyperexcitability in vitro, impairment of special learning in vivo, and an intact inhibitory system. Fifteen years after the discovery of Lis1's involvement in lissencephaly and ten years after the development of a mouse model for the disease, the basis of seizure generation remains a mystery. In this thesis I examined the excitatory system of the hippocampus, specifically CA1 pyramidal cells and their synaptic inputs. I found that the glutamatergic system is intact and functioning relatively normally; however, excitatory synaptic input onto CA1 pyramidal cells is nearly doubled in Lis1 +/- mutants. I also showed that the vesicular pool at excitatory synaptic contacts onto CA1 pyramidal cells is enlarged and importantly, the readily releasable pool (RRP) of synaptic vesicles is enlarged. I then examined the consequences of this change and found that Lis1 +/- mutants have enhanced short-term plasticity, which may underlie hyperexcitability and ultimately seizure generation in these mice. Finally, I showed that reducing calcium entry in these terminals eliminates this excitability. These data suggest a molecular basis for seizure generation in the lissencephalic brain and offer a new way to approach treatment for this disease.