Progressive increase of lysosomal enzyme activities in hippocampus associated with reduction of population spike in a rat model of neurodegeneration.

OBJECTIVES: Extensive effort has been made to identify early markers of neurodegeneration as late stages have no chance of treatment. Recently, many experimental models have been used to study hallmarks of neuronal injury. One of them is the model of trimethyltin (TMT)-induced damage associated with cognitive decline, thus called a model of Alzheimer-like disease.

OBJECTIVE AND METHODS: Our aim was to study neuronal transmission in hippocampal slices of male Wistar rats affected with a single dose of TMT (7.5 mg/kg, i.p.) during the first three weeks of its action. The monitored time periods after TMT administration were days 1-3; 8-10 and 15-17. At the same time periods, right hippocampi were collected for determination of changes in specific activities of two lysosomal enzymes. Electrophysiological measurements were based on stimulation of Schäffer collaterals and registration of evoked responses in the stratum pyramidale and the stratum radiatum at the CA3-CA1 synapse. Specific activities of N-acetyl-β-D-glucosaminidase (NAGA) and cathepsin D (Cat D) were determined spectrophotometrically.

RESULTS: During three weeks after i.p. TMT administration to rats, we found a time-dependent reduction of postsynaptic neuronal firing, expressed by diminished population spike (PoS) amplitude recorded in the stratum pyramidale accompanied with marked increase in specific activity of NAGA to respective 111%, 163% and 252% in the 1st, 2nd and 3rd week compared to unaffected rats. In the stratum radiatum, reduction of the slope of excitatory postsynaptic potential was not time-dependent but almost constantly reduced from the 1st to 3rd week after TMT administration (55-60%) compared to control rats. Specific activity of lysosomal enzyme Cat D was significantly increased in the 3rd week after TMT administration.

CONCLUSION: This work demonstrates a time-dependent reduction of somatic response in the hippocampus of TMT affected rats during the first three weeks. This reduction of neuronal firing was later accompanied with increase of specific activity of NAGA and Cat D, supporting evidence that lysosomal dysfunction may be one of the primary contributors to TMT-induced neurodegeneration.