Neuroscience

FAM72 is a novel neuronal progenitor cell (NPC) self-renewal supporting protein expressed under physiological
conditions at low levels in other tissues. Accumulating data indicate the potential pivotal tumourigenic effects of
FAM72. Our in silico human genome-wide analysis (GWA) revealed that the FAM72 gene family consists of four
human-specific paralogous members, all of which are located on chromosome (chr) 1. Unique asymmetric
FAM72 segmental gene duplications are most likely to have occurred in conjunction with the paired genomic
neighbour SRGAP2 (SLIT-ROBO Rho GTPase activating protein), as both genes have four paralogues in humans
but only one vertebra-emerging orthologue in all other species. No species with two or three FAM72/SRGAP2
gene pairs could be identified, and the four exclusively human-defining ohnologues, with different mutation
patterns in Homo neanderthalensis and Denisova hominin, may remain under epigenetic control through long
non-coding (lnc) RNAs.

Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late-onset HD phenotype. Here, we assessed refrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination onsisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex were studied in 4- to 5-month-old rats. Input/output curves, paired-pulse function, and plasticity induced by theta-burst stimulation (TBS) were assessed. Results showed an altere...

The ZnT3 zinc transporter is uniquely expressed in cortical glutamatergic synapses where it organizes zinc release into the synaptic cleft and mediates beta-amyloid deposition in transgenic mice. We studied the association of zinc in plaques in relation to cytoarchitectural zinc localization in the APP/PS1 transgenic mouse model of Alzheimer's disease. The effects of low dietary zinc for 3 months upon brain pathology were also studied. We determined that synaptic zinc distribution within cortical layers is paralleled by amyloid burden, which is heaviest for both in layers 2-3 and 5. ZnT3 immunoreactivity is prominent in dystrophic neurites within amyloid plaques. Low dietary zinc caused a significant 25% increase in total plaque volume in Alzheimer's mice using stereological measures. The level of oxidized proteins in brain tissue did not changed in animals on a zinc-deficient diet compared with controls. No obvious changes were observed in the autometallographic pattern of ...

The position of scaphopods in molluscan phylogeny remains singularly contentious, with several sister relationships supported by morphological and phylogenomic data: Scaphopoda + Bivalvia (Diasoma), Scaphopoda + Cephalopoda (Variopoda), and Scaphopoda + Gastropoda. Nervous system architecture has contributed significant insights to reconstructing phylogeny in the Mollusca and other invertebrate groups, but a modern neurophylogenetic approach has not been applied to molluscs, hampered by a lack of clearly defined homologous characters that can be unequivocally compared across the radical body plan disparity among the living clades. We present the first three-dimensional reconstruction of the anterior nervous system of a scaphopod, Rhabdus rectius, using histological tomography. We also describe a new putative sensory organ, a paired and pigmented sensory mantle slit. This structure is restricted to our study species and not a general feature of scaphopods, but it forms an integral part of the description of the nervous system in R. rectius. It also highlights the potential utility of neuro-anatomical characters formultiple levels of phylogenetic inference beyond this study. This potential has not previously been exploited for the thorny problem of molluscan phylogeny. The neuroanatomy of scaphopods demonstrates a highly derived architecture that shares a number of key characters with the cephalopod nervous system, and supports a Scaphopoda?Cephalopoda grouping.

We found that a single week of exercise enhanced cognitive function on the Morris water maze (MWM), such that exercise animals were significantly better than sedentary controls at learning and recalling the location of the platform. In order to elucidate the role that calcium calmodulin protein kinase II (CAMKII) holds in mediating the exercise-induced enhancement in learning and memory, a specific antagonist of CAMKII, KN-62, was used to block CAMKII in the rat hippocampus during a 1-week voluntary exercise period. Following, a two-trial-per-day MWM was performed for five consecutive days, succeeded by a probe trial 2 days later. Inhibiting CAMKII action during exercise blocked the ability of exercise to enhance memory retention on the MWM; the recall abilities of exercise animals receiving the CAMKII blocker were significantly worse than those of both sedentary and exercise controls. Conversely, CAMKII may not play a significant role in mediating the effects of exercise on learning acquisition as inhibiting CAMKII failed to block the exercise-induced enhancement in learning acquisition. Our results also show that CAMKII activation early during MWM learning may be counterproductive to learning acquisition, as exercising animals given the CAMKII inhibitor performed significantly (P<0.001) better than exercising control animals and sedentary controls only on day 2 of the MWM. Inhibiting CAMKII also blocked the exercise-induced upregulation of molecules critical for learning and memory, brain-derived neurotrophic factor (BDNF) and the transcription activator cAMP response-element-binding protein, which is regulated by and downstream to BDNF action. These findings indicate that hippocampal CAMKII may have a refined role in mediating the effects of exercise on cognition, selectively functioning to regulate memory retention.

We investigated whether the nucleus basalis lesion induced by quisqualic acid was associated with a more severe impairment of spatial navigation in a water maze, a greater reduction in frontal choline acetyltransferase activity and decrease in the number of choline acetyltransferase-positive neurons in the nucleus basalis in apolipoprotein E-deficient mice than in control mice. We also studied the effect of ageing on water maze spatial navigation and cortical choline acetyltransferase activity in 16-month-old control and apolipoprotein E-deficient mice. We found that the lesion decreased choline acetyltransferase-positive neurons in the nucleus basalis and frontal choline acetyltransferase activity equally in control and apolipoprotein E-deficient mice. The nucleus basalis lesion had no effect on the initial acquisition in the water maze in control and apolipoprotein E-deficient mice after 25 or 106 days of recovery. However, the nucleus basalis lesion impaired the reversal learning in the water maze similarly in both strains after 25 days of recovery, but had no effect after 106 days of recovery. Finally, water maze spatial navigation and cortical choline acetyltransferase activity were similar in old control and apolipoprotein E-deficient mice. These results suggest that young and old apolipoprotein E-deficient mice do not have impairments in cholinergic activity or spatial navigation. Furthermore, apolipoprotein E deficiency does not increase the sensitivity to cholinergic and spatial navigation deficits induced by lesioning of the nucleus basalis with an excitatory amino acid and does not slow down the behavioral recovery.

Polymorphisms in the Nicastrin (NCSTN) gene have recently been associated with familial early-onset Alzheimer's disease (AD). The authors genotyped four NCTSN polymorphisms in a large cohort of 489 AD cases (including 158 sporadic early-onset AD cases and 95 familial early-onset AD cases) and 386 controls but failed to replicate the association between NCSTN haplotype B and AD.

Alzheimer's disease (AD) is a genetically complex neurodegenerative disorder and the leading cause of dementia of the elderly. Recently, Hu et al. suggested that a trinucleotide deletion in intron 13 of the APBB1 gene was a factor protecting against late-onset AD. We report here the results of a case/control study aimed at replicating this association. Our study included 461 AD patients and 397 matched controls. We compared the allele and genotype frequencies of the polymorphism between the two groups but did not find any statistically significant difference (P=0.08 and P=0.09, respectively). By contrast, adjusting for age and sex, we found a slight risk associated with the deletion (odds ratio=1.47, 95% confidence interval=1.05-2.04). Stratification by age showed that the risk effect associated with the deletion concerned subjects aged less than 65 years.

Mutations in the gene for presenilin 1 are causative for the majority of cases of early onset familial Alzheimer's disease. Yet, the physiological function of presenilin 1 and the pathological mechanisms of the mutations leading to Alzheimer's disease are still unknown. To analyse potential pathological effects of presenilin 1 over-expression, we have generated transgenic rats which express high levels of human presenilin 1 protein in the brain. The over-expression of presenilin 1 leads to saturation of its normal processing and to the appearance of full-length protein in the transgenic rat brain. The transgenic protein is expressed throughout the brain and is predominantly found in neuronal cells. Cultured primary cortical neurons derived from these transgenic rats are significantly more sensitive than non-transgenic controls to apoptosis induced by standard culture conditions and to apoptosis induced by trophic factor withdrawal. Furthermore, the observed apoptosis is directly correlated with the expression of the transgenic protein. The results further emphasize the role of presenilin 1 in apoptotic cell death in native neuronal cultures.

We investigated the effect of the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (1 or 3 x 50 mg/kg, intraperitoneally), on hippocampal, cortical and cerebellar noradrenaline levels after recovery of one, five and 11 months in control and apolipoprotein E-deficient mice. Apolipoprotein E-deficient mice had lower hippocampal noradrenaline levels than control mice. DSP-4-lesioned control mice had a more extensive recovery of hippocampal and cortical noradrenaline levels than DSP-4-lesioned apoE-deficient mice after five months' survival. Furthermore, the hippocampal noradrenaline levels after five and 11 months and cortical noradrenaline levels after five months of recovery had slightly recovered in control but not in apolipoprotein E-deficient mice treated with a single dose of DSP-4 compared with mice treated with three doses of DSP-4. These results show that apolipoprotein E-deficient mice have impaired recovery capacity in their locus coeruleus neurons.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motoneurons, and has no effective treatment. Experimental studies in rodents have shown that motoneurons respond to a variety of molecules including brain-derived neurotrophic factor (BDNF). and the glial-cell line-derived neurotrophic factor (GDNF). Here we investigated the neuroprotective effect of these growth factors, encoded by an adenovirus, on the death of axotomized facial motoneurons in newborn rats. We used a new gene therapy strategy that involves gene transfer to motoneurons by intramuscular injection of an adenoviral vector, which is retrogradely transported from injected target muscle (Finiels et al.,: NeuroReport 7:373-378, 1995). A significant increased survival of motoneurons was observed in animals pretreated with adenovirus encoding BDNF (34.5%, P < 0.05) ou GDNF (41.9%, P < 0.05) 1 week after axotomy. These results indicate that pretreatment with BDNF or GDNF, using this therapeutic strategy, is able to prevent the massive death of motoneurons that normally follows axotomy in the neonatal period, opening new perspectives to limit neuronal death in degenerative disorders.

The superoxide dismutase 1 (SOD1)G93A mouse was recently established as transgenic model of amyotrophic lateral sclerosis. We were interested to know whether the SOD1 G93A mutation promotes neuronal injury after intraluminal middle cerebral artery thread occlusion and/or retinal ganglion cell (RGC) axotomy in mice, which are highly reproducible and clinically relevant in vivo models of acute and subacute neuronal degeneration, respectively. In our experiments, G93A mutant SOD1 neither influenced ischemic injury after 90 or 30 min of focal ischemia, nor had an impact on the severity of RGC degeneration after optic nerve transection, when human SOD1 G93A mutant mice were compared to human wild-type SOD1 mice. Our data indicate that the clinically relevant SOD1 G93A mutation, which leads to amyotrophic lateral sclerosis in humans and mice, does not necessarily worsen neuronal degeneration in other pathologies. Thus, the G93A mutation may be counterbalanced in non-motor neurons of young...

The role of adenosine deaminase in the interactions between adenosine A(1) and dopamine D(1) receptors was studied in a mouse fibroblast cell line stably cotransfected with human D(1) receptor and A(1) receptor cDNAs (A(1)D(1) cells). Confocal laser microscopy analysis showed a high degree of adenosine deaminase immunoreactivity on the membrane of the A(1)D(1) cells but not of the D(1) cells (only cotransfected with human D(1) receptor cDNAs). In double immunolabelling experiments in A(1)D(1) cells and cortical neurons a marked overlap in the distribution of the A(1) receptor and adenosine deaminase immunoreactivities and of the D(1) receptor and adenosine deaminase immunoreactivities was found. Quantitative analysis of A(1)D(1) cells showed that adenosine deaminase immunoreactivity to a large extent colocalizes with A(1) and D(1) receptor immunoreactivity, respectively. The A(1) receptor agonist caused in A(1)D(1) cells and in cortical neurons coaggregation of A(1) receptors and adenosine deaminase, and of D(1) receptors and adenosine deaminase. The A(1) receptor agonist-induced aggregation was blocked by R-deoxycoformycin, an irreversible adenosine deaminase inhibitor. The competitive binding experiments with the D(1) receptor antagonist [(3)H]SCH-23390 showed that the D(1) receptors had a better fit for two binding sites for dopamine, and treatment with the A(1) receptor agonist produced a disappearance of the high-affinity site for dopamine at the D(1) receptor. R-Deoxycoformycin treatment, which has previously been shown to block the interaction between adenosine deaminase and A(1) receptors, and which is crucial for the high-affinity state of the A(1) receptor, also blocked the A(1) receptor agonist-induced loss of high-affinity D(1) receptor binding. The conclusion of the present studies is that the high-affinity state of the A(1) receptor is essential for the A(1) receptor-mediated antagonistic modulation of D(1) receptors and for the A(1) receptor-induced coaggregates of A(1) and adenosine deaminase, and of D(1) and adenosine deaminase. Thus, the confocal experiments indicate that both A(1) and D(1) receptors form agonist-regulated clusters with adenosine deaminase, where the presence of a structurally intact adenosine deaminase bound to A(1) receptors is important for the A(1)-D(1) receptor-receptor interaction at the level of the D(1) receptor recognition.