EPILEPTIFORM EEG ACTIVITY AND PRE-PULSE INHIBITION IN PHENYLKETONURIA

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Phenylketonuria (PKU) is one of the most common inborn errors of metabolism. The underlying mutations in the phenylalanine hydroxylase (Pah) gene cause an accumulation of phenylalanine (Phe) and its metabolites on both sides of the blood-brain barrier, resulting in a spectrum of neurologic and neuropsychologic symptoms. These symptoms are related to the degree of dietary control and range from mental retardation and seizures in classical PKU to deficits in attentional flexibility and executive function even in early-treated PKU patients. Despite tremendous progress in understanding the molecular basis of PKU, the mechanism(s) whereby hyperphenylalaninemia results in brain dysfunction are not known. We have recently demonstrated that acute applications of L-Phe, at a range of concentrations found in PKU brain, selectively depress glutamatergic synaptic transmission (GST) in rat and mouse hippocampal and cerebrocortical cultured neurons at pre- and postsynaptic sites, but do not affect gamma-aminobutyric (GABA)-ergic activity. Consistent with selective depression of GST in vitro, the expression and density of glutamate receptors, but not GABA receptors, were significantly increased in the forebrains of PKU (Pahenu2) mice, providing evidence that glutamatergic synaptic transmission in PKU brain is impaired. These results and literature data suggest that impaired glutamatergic synaptic transmission underlies (or contributes to) the neurologic and neuropsychologic manifestations of PKU. One manifestation of PKU that is shared by schizophrenia is the inability to ignore irrelevant or redundant stimuli. This inability is referred to as a sensori-motor gating deficit and may be a component underlying deficits in executive function. A sensori-motor gating deficit can be assessed by using the pre-pulse inhibition (PPI) paradigm. PPI refers to the decreased response to a stimulus (pulse) sufficiently intense to elicit a startle response when this stimulus is immediately preceded by a weaker pre-stimulus (pre-pulse). Interventions that depress GST have been shown to increase PPI. Given the pivotal role of L-Phe for the degree to which classical PKU manifests in vivo and given that acute application of L-Phe impairs GST whereas withdrawal elicits excitatory phenomena in vitro, we hypothesize that changes in L-Phe plasma concentrations parallel changes excitatory epileptiform electroencephalographic activity, changes in PPI, and changes in executive function in PKU patients, who alter dietary control.