Epidemiological studies suggest that early in life, the brain is very susceptible to seizures and especially status epilepticus (SE). Understanding the spectrum and progressive nature of SE-induced changes in brain function may have important implications in the design of treatments aimed at disease modification. The substantia nigra pars reticulata (SNR) is one of the brain sites critically involved in the control of seizures. Preliminary data indicate that the development of the SNR is distorted if infant rats experience 3 episodes of SE (3SE) prior to postnatal day (PN) 6 by preventing the emergence of the SNR GABA-sensitive anticonvulsant region at PN30. 3SE are not associated with acute neuronal injury in SNR but increase the expression of the chloride cotransporter KCC2 mRNA and accelerate the switch of synaptic GABAAergic responses from depolarizing to hyperpolarizing;induce changes in GABAA receptor subunit composition;and attenuate the responsiveness of SNRanterior neurons to GABAA agents in vivo and in vitro at PN30. Because the depolarizing effects of GABA are important for neuronal differentiation, the data suggest that, during a specific developmental window, the 3SE- induced increases in KCC2 expression and the resultant early appearance of hyperpolarizing responses may shorten the period during which the normal GABA-mediated differentiation of SNR occurs.
The specific aims are to determine: 1. The discrete developmental periods during which exposure to 3SE prevents the expression of SNR GABAA-sensitive anticonvulsant region;2. The effects of 3SE during the susceptible developmental period on GABAA-related function in SNR;3. The identification of agents that can restore the normal developmental pattern of GABAA receptor signaling and avert the 3SE-induced long-term detrimental effects on SNRanterior GABAA-sensitive anticonvulsant region. Male and female rats will be used. Methods include induction of SE using kainic acid or pilocarpine, intracranial microinfusions of GABAA agents and seizure testing using flurothyl or pentylenetetrazole, immunohistochemistry, qRT-PCR, in situ hybridization, in vivo and in vitro electrophysiological recordings.
The overall goal is to identify mechanisms involved in the suppression of seizures as a function of age, gender and prior history of seizures. Recurrent prolonged seizures may prevent the normal maturation of the brain. Understanding the impact of these seizures on the development of effective seizure suppressing mechanisms in animals may lead to the identification of new time-sensitive treatments to prevent the long-term effects of status epilepticus in human infants.
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