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Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause Lafora disease (LD), a progressive and invariably fatal epilepsy with periodic acid-Schiff-positive (PAS+) cytoplasmic inclusions (Lafora bodies) in the central nervous system. To study the pathology of LD and the functions of laforin, we disrupted the Epm2a gene in mice. At two months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibit swelling in the endoplasmic reticulum, Golgi networks and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies become more prominent at 4-12 months, organelles and nuclei are disrupted. The Lafora bodies, present both in neuronal and non-neural tissues, are positive for ubiquitin and advanced glycation end-products only in neurons, suggesting different pathological consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predate the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity. Our results suggest that LD is a primary neurodegenerative disorder that may utilize a non-apoptotic mechanism of cell death.

Animals vary in their sensitivity to ethanol, a trait at least partly determined by genetic factors. In order to identify possible responsible genes, mice lacking Fyn, a non-receptor type tyrosine kinase, were investigated. These mice were hypersensitive to the hypnotic effect of ethanol. The administration of ethanol enhanced tyrosine phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) in the hippocampus of control mice but not in Fyn-deficient mice. An acute tolerance to ethanol inhibition of NMDAR-mediated excitatory postsynaptic potentials in hippocampal slices developed in control mice but not in Fyn-deficient mice. These results indicate that Fyn affects behavioral, biochemical, and physiological responses to ethanol.

Ethanol affects many functions of the brain and peripheral organs. Here we show that ethanol opens G-protein-activated, inwardly rectifying K + (GIRK) channels, which has important implications for inhibitory regulation of neuronal excitability and heart rate. At pharmacologically relevant concentrations, ethanol activated both brain-type GIRK1/2 and cardiac-type GIRK1/4 channels without interaction with G proteins or second messengers. Moreover, weaver mutant mice, which have a missense mutation in the GIRK2 channel, showed a loss of ethanol-induced analgesia. These results suggest that the GIRK channels in the brain and heart are important target sites for ethanol.

In order to analyze the functions of the hippocampus in the primate, and to advance the understanding of amnesia, the activity of 994 single hippocampal neurons in the monkey was analyzed during the performance of a task known to be affected by hippocampal damage in which both an object, and its position in space, must be remembered. The serial multiple object-place memory task required a memory for the position on a video monitor in which a given object had appeared previously. It was found that 9.3% of neurons recorded in the hippocampus and hippocampal gyrus had spatial fields in this and related tasks, in that they responded whenever there was a stimulus in some but not in other positions on the screen. We found that 2.4% of the neurons responded to a combination of spatial information and information about the object seen, in that they responded more the first time a particular object was seen in any position. Six of these neurons were found that showed this combination even more clearly, in that, for example, they responded only to some positions and only if it was the first time that a particular stimulus had appeared there. It is concluded that there are neurons in the primate hippocampus which (1) respond to position in space and (2) in some cases combine information about stimuli and their position in space, responding to a stimulus only the first time it is seen in a position in space, for example. Thus, not only is spatial information processed by the primate hippocampus, but it can be combined with information about which stimuli have been seen before. The ability of the hippocampus to form such conjunctions may be an important property for its role in memory.

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