Disorders of neuronal migration are a group of developmental brain anomalies that include cortical dysplasia and neuronal heterotopia. There is a strong association between these disorders and intractable epilepsy in humans but relatively little is known about their physiologic properties and how they produce seizures. This project will use an animal model to produce cortical dysplasia and neuronal heterotopia in rats by exposing them to low doses of gamma-irradiation in utero in order to determine if there are alterations in excitatory and inhibitory connectivity in these areas that would produce an increased propensity for seizures in these animals. Fetal rats will be irradiated in utero in order to produce areas of cortical dysplasia and neuronal heterotopia. They will then be tested at ages 3.5 to 4.5 weeks. Whole-cell patch clamp recordings will be obtained from neurons in dysplastic and heterotopic cortex and compared to those from control neocortex. Neurons will be classified into 4 types according to whether they are excitatory or inhibitory and their intrinsic firing properties (regular spiking, intrinsic bursting, fast spiking, low threshold spiking). This will serve as the basis for comparing appropriate types of neurons between the three types of cortex. Excitatory connectivity in dysplastic and heterotopic cortex and control neocortex will be evaluated by recording spontaneous and stimulus-evoked excitatory post-synaptic currents in physiologic solution. Excitatory synaptic events will also be measured during and in between epileptiform bursts that occur with blockade of A-type gamma-aminobutyric acid receptors. Inhibitory systems in the local circuitry will be evaluated by recording inhibitory post-synaptic currents in physiologic solution. Two types of stimulus-evoked inhibitory synaptic events will also be measured. Polysynaptic events will be elicited by stimulating the adjacent white matter in physiologic solution. Monosynaptic inhibitory currents will be elicited by stimulating cells near the recording electrode in the presence of antagonists of excitatory amino acid receptors. Immunohistochemical studies will be performed to quantify the number of inhibitory neurons in dysplastic and heterotopic cortex compared to control neocortex. Antibodies for glutamic acid decarboxylase, parvalbumin, and calbindin- D28k will be used to identify these cells. Quantitative, stereologic methods will be used to determine numbers of the cell types in each type of cortex. These will be compared to total neuronal numbers to determine if there is a preferential loss of inhibitory neurons in these areas. The information gained from these studies will test specific hypotheses concerning alterations in connectivity, excitatory and inhibitory neural transmission, and firing properties of neurons in areas of cortical dysplasia and neuronal heterotopia in order to improve our understanding of how disorders of neuronal migration produce intractable epilepsy and provide the groundwork for devising more effective medical and surgical treatments for this devastating problem.
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