Abstracts

The mechanisms underlying epileptic activity in untreated phenylketonuria (PKU) patients are not well understood. Based on our previous findings that phenylalanine (Phe) at concentrations found in PKU mouse brain significantly and reversibly depresses glutamatergic synaptic transmission leading to a compensatory increase in the expression and density of glutamate receptors, we hypothesized that seizures in PKU mice might be observed when Phe levels are decreased and glutamatergic activity becomes facilitated., This hypothesis was tested by examining the susceptibility of PKU mice (female homozygous [italic]Pah[/italic]^enu2 BTBR) to audiogenic seizures (AGS) induced by sound stimulus of 118 dB (10-20 kHz)., Serum Phe concentrations in PKU mice were more than 10 fold higher than in heterozygous (HET) carriers or wild-type (WT) BTBR mice. Unlike HET carriers or WT mice, adult PKU mice, 8 weeks of age or older, were susceptible to AGS and exhibited dramatic responses with symptoms ranging from uncontrolled running to clonic and tonic convulsions, respiratory arrest, and death. Death could be prevented by pretreatment with oxygen-enriched air. Serum Phe levels in PKU mice could vary significantly with time of day, with an average decrease of 0.53 mM from 9 am to 5 pm. Depending on Phe levels, the same mouse could be either susceptible or resistant to AGS. In general, while adult mice with Phe levels of less than 2 mM routinely exhibited AGS, mice with Phe levels of greater than 2 mM were resistant to the stimulus. Young PKU mice consistently had significantly higher serum Phe levels and were not susceptible to AGS. Serum Phe levels in adult PKU mice could be lowered to normal, or increased to hyperphenylalaninemic concentrations within 12 hours, by switching adult PKU mice from a high to low Phe diet, or vice versa. Susceptibility to AGS disappeared after 12 hours on the low Phe diet. In contrast, more than 7 weeks on a standard diet were necessary before PKU mice, previously maintained for two weeks on a low Phe diet, regained susceptibility to AGS., Complex dependence of AGS on Phe levels indicates that the Phe-induced changes in glutamatergic synaptic transmission may play an important etiological role in PKU seizures. If seizure susceptibility is similarly reversible in human PKU patients, then they may face a risk of becoming susceptible to seizures after relaxing their Phe-restricted diet, perhaps especially with increasing age. Given the known mutation and the well defined biochemical background, the [italic]Pah[/italic]^enu2 mouse may become a new valuable model for investigating the mechanisms underlying epileptic activity in general., (Supported by NIH DK058327 (PJL), the University of Florida McKnight Brain Institute, and I. Heermann Anesthesia Foundation, Inc.)