Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.

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Most of the research on ventral striatal functions has been focused on their role in modulating reward and motivation. More recently, a possible role of this structure in cognitive functions has been suggested. However, very little information is available on the involvement of the nucleus accumbens in the different stages of the consolidation process. In this study, the effect of focal injections of AP-5 and DNQX, competitive antagonists at the NMDA and AMPA receptors, respectively, was examined in a nonassociative task designed to estimate the ability of mice to react to spatial changes. The task consists of placing the animals in an open field containing five objects; after three sessions of habituation, their reactivity to object displacement was examined 24 hr later.AP-5 injections administered after training impaired the ability of mice to detect the spatial novelty but did not affect response when injected 120 min after training or before testing. On the contrary, DNQX did not affect response when administered immediately or 120 min after training but did impair spatial discrimination when administered before training or testing. These data demonstrate a double dissociation between glutamate receptor subtypes, such that accumbens NMDA receptors are important for consolidation and not ongoing discrimination of spatial information, whereas AMPA receptors have an opposite role in these processes.

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These results confirm that dopamine depletion is accompanied by cognitive deficits and demonstrate that striatal dopamine dysfunction is sufficient to induce spatial information processing deficits.