Title

Cellular properties, cortical circuitry and aberrant activity associated with focal neocortical dysplasias

Date of Completion

January 2001

Keywords

Biology, Neuroscience

Degree

Ph.D.

Abstract

Cortical malformations have been associated with cognitive impairments and epilepsy in humans. Several animal models of cortical dysplasia show that dysplasia causes increased seizure susceptibility and behavioral deficits in vivo, and increased levels of excitability in vitro. Small groups of displaced neurons in layer I of the neocortex, ectopias, have been identified in patients with cognitive impairments, and similar malformations occur sporadically in some inbred lines of mice where they are associated with behavioral and sensory processing deficits. Although there is a correlation between cortical malformations and neurological impairments the particular properties of dysplastic cortex that cause impaired function have not been clearly defined. Before we can examine potential causes of impaired function we first need to understand the cellular properties of ectopias. Electrophysiological and histological analysis revealed that neurons within ectopias display multiple types of action potential filing patterns, and morphological properties, including pyramidal and a variety of nonpyramidal cells. Ectopic cells have glutamatergic and GABAergic synapses, and receive direct excitatory and inhibitory input from adjacent normatopic cortex. Further examination of intracortical circuitry in slices containing ectopias reveal that although ectopic cells receive input from cells in all cortical layers of the normatopic cortex, they only send projections to neurons within deep cortical layers. Despite normal physiological properties of ectopic cells, aberrant activity was evident. Spontaneous epileptiform activity was shown to occur when multiple adjacent ectopias were present in a single slice. Using extracellular recordings from brain slices we show that even single layer I ectopias are associated with higher excitability. Specifically, slices that contain single ectopias display epileptiform activity at significantly lower concentrations of bicuculline than do slices without ectopias. We demonstrate that this enhanced excitability is not generated within ectopias, since removal of ectopias from slices does not restore normal excitability. Examination of seizure susceptibility in vivo showed that mice with ectopias are more sensitive to the convulsant pentylenetetrazole than are mice without ectopias These results suggest that alterations in slices containing ectopias increase cortical excitability in vitro and in vivo . In its entirety, the findings in this thesis enhance our understanding of cortical maldevelopment and the consequences of cortically dysplasia on neurological function. ^