Threshold for epileptiform activity is elevated in prion knockout mice.

Prion protein (PrP) is abundant in the nervous system, but its role remains uncertain. Prion diseases depend on an aggregation of the protein that is likely to interfere with its normal function. Loss of function does not in itself cause neurodegeneration, but whether it contributes to the clinical features of the disease remains an open question. Patients with classical Creutzfeldt-Jakob disease (CJD) have a higher than expected incidence of epilepsy. To study the mechanisms by which loss of PrP function may underlie changes in vulnerability to epilepsy in disease, we used several acute epilepsy models: we applied a variety of convulsant treatments (zero-magnesium, bicuculline, and pentylenetetrazol) to slices in vitro from PrP knockout (Prnp0/0) and control mice. In all three epilepsy models, we found that longer delays and/or higher concentrations of convulsants were necessary to generate spontaneous epileptiform activity in Prnp0/0 mice. These results together indicate an increased seizure threshold in Prnp0/0 mice, suggesting that loss of PrP function cannot explain a predisposition to seizures initiation in CJD.

Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration.

Prion protein (PrP) plays a crucial role in prion disease, but its physiological function remains unclear. Mice with gene deletions restricted to the coding region of PrP have only minor phenotypic deficits, but are resistant to prion disease. We generated double transgenic mice using the Cre-loxP system to examine the effects of PrP depletion on neuronal survival and function in adult brain. Cre-mediated ablation of PrP in neurons occurred after 9 weeks. We found that the mice remained healthy without evidence of neurodegeneration or other histopathological changes for up to 15 months post-knockout. However, on neurophysiological evaluation, they showed significant reduction of afterhyperpolarization potentials (AHPs) in hippocampal CA1 cells, suggesting a direct role for PrP in the modulation of neuronal excitability. These data provide new insights into PrP function. Furthermore, they show that acute depletion of PrP does not affect neuronal survival in this model, ruling out loss of PrP function as a pathogenic mechanism in prion disease and validating therapeutic approaches targeting PrP.

Synapse distribution of olfactory interneurons in the procerebrum of the snail Helix aspersa.

The procerebrum is believed to be important for processing olfactory information and storing olfactory memories in terrestrial pulmonate molluscs. Previous results have demonstrated that the procerebral cell population is morphologically heterogeneous. In the present study, serial sections and electron microscopy were used to investigate differences in synapse distributions. The results demonstrate that procerebral neurons with different sites of arborization have distinct patterns of synapse distribution that probably reflect different functional contributions to the olfactory pathway. Cells that have all their arborizations in the procerebrum, but none in the internal mass, have multiple large varicosities that are specialized for output. On the other hand, cells that arborize in the internal mass or outside the procerebrum have mostly input synapses proximal to the soma and mostly output synapses in the terminal region of the neurites. These cells appear to transmit information from the procerebral cell body mass to other central nervous system regions, e.g., the internal mass and the mesocerebrum. The implications of these data are twofold. Firstly, the procerebrum directly participates in distributing processed olfactory information to more central regions of the nervous system. Secondly, the procerebral neuronal population may be divisible into two subgroups: 1) intrinsically arborizing interneurons; and 2) projection neurons. This is significant because the neural organization of the procerebrum may now be compared with that of olfactory systems in other organisms.

Impaired anticipatory finger grip-force adjustments in a case of cerebellar degeneration.

We describe adjustments in grip force as a consequence of fluctuations in inertial load force during vertical movements of the upper limb in a patient with cerebellar degeneration. Normally grip force is adapted to load-force fluctuations, in particular to the maximum load force, which occurs early in upward movements and late in downward movements. Increased grip force during movement was observed in the patient, but the timing of maximum grip force was not different between upward and downward movements. This suggests impaired cerebellar prediction of the dynamic consequences of voluntary movement.

Morphology of interneurons in the procerebrum of the snail Helix aspersa.

Terrestrial snails have a highly developed sense of olfaction. Because the procerebrum has a large number of cells and is located at the entry site of the olfactory nerve into the brain, the structure is thought to have a significant role in the processing of olfactory stimuli. The morphology of the procerebral neurons in the snail Helix aspersa was investigated through intracellular injections of biocytin. No formal categorization of neuronal types was possible, but some cells were seen to have neurites entirely intrinsic to the procerebrum, whereas others had both intrinsic and extrinsic arborizations, and still others had only extrinsic arborizations. These interneurons were previously thought to have arborizations restricted to the procerebral lobe. We demonstrated the extent of the neurite projections outside of the procerebral lobe by making focal injections of biocytin or Neurobiotin into various regions of the cerebral ganglion. This technique revealed subsets of cells that send neurites not only in the ipsilateral ganglion but also through the cerebral commissure into the contralateral cerebral ganglion. Our results demonstrate not only that the procerebral cell population is heterogeneous but also that the procerebrum interacts more directly with the rest of the central nervous system than was formerly believed.

Triethyltin-produced decrease and recovery of wheel running and food-reinforced lever pressing in rats.

Behavioral effects of triethyltin were studied in rats living in Wahmann activity cages. Wheel running activity and food-reinforced lever pressing were recorded 23 hr/day from 4 rats. Triethyltin injections (4 mg/kg IP) produced large transient decreases in running, lever pressing, and daily water consumption, without affecting body weight. These measures recovered to pre-treatment levels within 1-2 days. After 4 weekly injections, wheel running was reduced in 2 rats, and increased in 1 rat, while lever pressing remained at baseline levels. Good correlation was noted between the extent of reductions in wheel running and lever pressing, and the extent of characteristic triethyltin-induced morphological lesions in the central and peripheral nervous system. Over the course of repeated treatments, several critical behaviors known to be sensitive to neurotoxicants can be continually monitored using automated testing apparatus. While further validation with more compounds is required, these results suggest that monitoring wheel running, food-reinforced lever pressing, and water consumption may be an inexpensive way to test for behavioral neurotoxicity using small numbers of animals.