Tau- but not Aß -pathology enhances NMDAR-dependent depotentiation in AD-mouse models.

Many mouse models of Alzheimer's disease (AD) exhibit impairments in hippocampal long-term-potentiation (LTP), seemingly corroborating the strong correlation between synaptic loss and cognitive decline reported in human studies. In other AD mouse models LTP is unaffected, but other defects in synaptic plasticity may still be present. We recently reported that THY-Tau22 transgenic mice, that overexpress human Tau protein carrying P301S and G272 V mutations and show normal LTP upon high-frequency-stimulation (HFS), develop severe changes in NMDAR mediated long-term-depression (LTD), the physiological counterpart of LTP. In the present study, we focused on putative effects of AD-related pathologies on depotentiation (DP), another form of synaptic plasticity. Using a novel protocol to induce DP in the CA1-region, we found in 11-15 months old male THY-Tau22 and APPPS1-21 transgenic mice that DP was not deteriorated by Aß pathology while significantly compromised by Tau pathology. Our findings advocate DP as a complementary form of synaptic plasticity that may help in elucidating synaptic pathomechanisms associated with different types of dementia.

Separate Ionotropic and Metabotropic Glutamate Receptor Functions in Depotentiation vs. LTP: A Distinct Role for Group1 mGluR Subtypes and NMDARs.

Depotentiation (DP) is a mechanism by which synapses that have recently undergone long-term potentiation (LTP) can reverse their synaptic strengthening within a short time-window after LTP induction. Group 1 metabotropic glutamate receptors (mGluRs) were shown to be involved in different forms of LTP and long-term depression (LTD), but little is known about their roles in DP. Here, we generated DP by applying low-frequency stimulation (LFS) at 5 Hz after LTP had been induced by a single train of theta-burst-stimulation (TBS). While application of LFS for 2 min (DP2') generated only a short-lasting DP that was independent of the activation of N-methyl-D-aspartate receptors (NMDARs) and group 1 mGluRs, LFS given for 8 min (DP8') induced a robust DP that was maintained for at least 2 h. This strong form of DP was contingent on NMDAR activation. Interestingly, DP8' appears to include a metabotropic NMDAR function because it was blocked by the competitive NMDAR antagonist D-AP5 but not by the use-dependent inhibitor MK-801 or high Mg2+. Furthermore, DP8' was enhanced by application of the mGluR1 antagonist (YM 298198, 1 µM). The mGluR5 antagonist 2-Methyl-6(phenylethynyl) pyridine (MPEP, 40 µM), in contrast, failed to affect it. The induction of LTP, in turn, was NMDAR dependent (as tested with D-AP5), and blocked by MPEP but not by YM 298198. These results indicate a functional dissociation of mGluR1 and mGluR5 in two related and consecutively induced types of NMDAR-dependent synaptic plasticity (LTP → DP) with far-reaching consequences for their role in plasticity and learning under normal and pathological conditions.

Telencephalic histopathology and changes in behavioural and neural plasticity in a murine model for metachromatic leukodystrophy.

Arylsulfatase A-deficient (ASA(-/-)) mice constitute an animal model for metachromatic leukodystrophy, a lysosomal storage disorder. We had previously examined the behavioural phenotype of these mice, but were unable to distinguish between proper cognitive symptoms and potentially interfering, solely neuromotor impairments. In the present study, T-maze delayed alternation (TMDA) showed that ASA(-/-) mice perform worse than controls already at the age of 6 months in a hippocampus-dependent task that does not require motor proficiency. In addition, long term potentiation (LTP) in the CA1 region of the hippocampus, a cellular correlate of learning and memory, was also impaired in ASA(-/-) mice. Finally, histological analysis of previously unexamined telencephalic and diencephalic structures illustrated sulfatide accumulation in brain areas that are important for cognitive functioning. These include the hippocampus, striatum, internal capsule and diencephalon as well as prefrontal, insular, and motor and somatosensory cortices. Together these data corroborate the usefulness of the model in preclinical evaluations of therapeutic strategies that aim to reverse cognitive defects in the human disease.

Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis.

Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain. Here, we employed a novel combination of molecular strategies to find the responsible gene and show its effects in an animal model. Utilizing only three unrelated affected individuals and their relatives, we used homozygosity mapping with single-nucleotide polymorphism chips to localize AMRF. We then used microarray-expression analysis to prioritize candidates prior to sequencing. The disorder was mapped to 4q13-21, and microarray-expression analysis identified SCARB2/Limp2, which encodes a lysosomal-membrane protein, as the likely candidate. Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes. This study highlights that recessive genes can be identified with a very small number of subjects. The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF. The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies.

Escrita Latrinaria

Escrita latrinaria sao os grafitos encontrados nas paredes de banheiros publicos. O que motiva as pessoas a escreve-los? Que tipos de interesses aparecem mais frequentemente nos grafitos? Quem picha mais, o homem ou a mulher? Ha diferencas entre os sexos quanto ao conteudo dos grafitos produzidos? Estas foram algumas perguntas que motivaram a realizacao da presente pesquisa. A coleta de dados foi feita em banheiros de varias faculdades de uma universidade, em Sao Paulo. Cada grafito foi classificado em uma das 20 categorias: insulto racial, insulto sexual, insulto geral, humor sexual, humor geral, convite sexual, romantismo, politica, drogas, religiosidade, moralidade, nomes, higiene, problemas pessoais, gramatica, escatologicos, filosofia, aids, sexualidade e generalidades. No total, foram registrados 518 grafitos: 424 nos banheiros masculinos (82 por cento) e 94 nos femininos (18 por cento). A categoria predominante, para a amostra como um todo foi sexualidade (19 por cento). Agrupando-se as categorias sexualidade, convite sexual, humor sexual, insulto sexual e aids, a proporcao sobe para 41,1 por cento. Este resultado confirma as observacoes de Barbosa (1985), uma pesquisa realizada no inicio da decada de 80, de que as pichacoes latrinarias mais comuns sao as relacionadas a sexualidade. Diferencas especificas, no entanto, podem ser apontadas. Preocupacao com aids nao era encontrada nos banheiros publicos no inicio da decada de 80, tendo sido encontrada na presente pesquisa. A categoria imediatamente mais frequente apos a sexualidade foi politica, tanto para os homens ( 15 por cento) como para as mulheres (14,9 por cento). Foram encontradas diferencas entre os sexos: nos banheiros femininos as categorias romantismo, problemas pessoais e moralidade foram mais frequentes que nos masculinos; ja as categorias convite sexual, insulto geral e insulto sexual foram mais frequentes nos banheiros masculinos que nos femininos.