Search

Consumption of caffeine, a non-selective adenosine A2Areceptor (A2AR) antagonist, reduces the risk of developing Alzheimer’s disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2Areceptors as important molecular targets to consider against AD and Tauopathies.

Summary.: Nephrectomy in mice provokes a decrease in creatinine clearance (CTNCl) and an increase in urea and specific guanidino compound (GC) concentrations in blood and other tissues. Our purpose was to investigate the influence of high protein diet (HPD) on CTNCl, urea and GC levels in NX mice. Mice were nephrectomized or sham-operated and subdivided in groups to study five diet conditions. At the end of each experiment, 10 days and 30 days postsurgery, urine and blood were collected for determination of urea and GCs, including creatinine. HPD resulted in significantly higher CTNCl values in sham-operated mice than those observed in mice under normal protein diet, 10 days as well as 30 days postnephrectomy. HPD induced significant increases in plasma urea, guanidinosuccinic acid, argininic acid and α-keto-δ-guanidinovaleric acid concentration 10 days postsurgery but not 30 days postsurgery. HPD coincided with significantly higher excretion of urea, guanidinosuccinic acid, α-keto-δ-guanidinovaleric acid, creatine, argininic acid and γ-guanidinobutyric acid in sham-operated and nephrectomized mice 10 days postsurgery. Our results show that HPD induces supplementary (to nephrectomy) increases of urea and GCs in the early postsurgery period but not in the later phase.

Background:This study investigates the effect of nephrectomy in young and aged mice on some biochemical, histological and behavioural aspects. Methods:Each age group, 2- and 12-months-old, comprised a sham-operated group, a unilaterally nephrectomized group and a subtotally nephrectomized group. Consequences of nephrectomy were examined 10 days postsurgery on urea and guanidino compound levels in body fluids and brain; the remaining kidney by light-microscopic examination; and learning and memory abilities using the Morris water maze task. Results:Effect of nephrectomy on urea and guanidino compound levels in plasma, urine and brain was significantly more pronounced in the young age group. Some guanidino compounds show a tendency to decrease with aging in the sham-operated group and the two nephrectomized groups. Higher compensatory kidney hypertrophy was found in younger nephrectomized mice whereas in older mice glomerular mesangial expansion was a common feature. Finally, young mice with subtotal nephrectomy displayed a slight but significant impairment in memory and learning; whilst old nephrectomized mice manifested no impairment. Conclusions:Nephrectomy induces more changes in younger mice than in older mice as observed in higher variation of urea and guanidino compound levels, glomerular volume and kidney hypertrophy and decline in spatial learning and memory.

Summary.: Amino acid and biogenic amine changes were investigated in nephrectomized mice ten days postsurgery. Uremic mice exhibited changes in amino acid concentrations in plasma, urine and brain. Particularly plasma methionine, citrulline and arginine levels were significantly enhanced in nephrectomized mice compared to controls whereas serine was decreased. Urinary excretion of methionine, citrulline and alanine was higher in nephrectomized mice compared to controls whereas many amino acids were increased in brain of nephrectomized mice. Brain and urinary amino acid changes were more pronounced in the 75% than in the 50% nephrectomized mice. Brain norepinephrine and dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were significantly increased whereas serotonin was decreased comparing the 75% nephrectomized mice to the sham-operated mice. This study demonstrates that at very early stages of renal insufficiency, specific amino acid and biogenic amine changes occur in plasma, urine and brain. These alterations might depend qualitatively and quantitatively on the degree of functional renal mass reduction.

Animal models serve to imitate (patho)physiological states known to occur in target species (usually man but sometimes other species as well). The use of animal models has had and may continue to have a tremendous impact on medical progress. Laboratory animals are now used in the study of basic (patho)physiological mechanisms, in the development, production and evaluation of therapeutic and diagnostic agents, in safety studies to assess carcenogenic, teratogenic or reproductive toxicity of investigational agents, and in education and training. The quality or utility of a model often depends upon its validity, which is highest in so-called homologous models where the symptoms displayed as well as the cause of the condition in the animal are identical to those of the human condition. Isomorphic models display similar symptoms, but the condition is not provoked by the same events as the human condition. Partial models do not attempt to model the entire condition, but focus only on limited aspects. Models can be further classified into spontaneous, induced, negative and “orphan” models. Uncritical extrapolation of animal findings to the human condition may lead to unreliable or even dangerous conclusions. Extrapolation tends to be most reliable when a plurispecies approach is taken, and when differences in metabolic patterns and speed as well as several other confounding variables are taken into account. Animal models have been crucial to neurological and psychiatric research, even though the search for valid models has been difficult in these fields because of the differences in brain structure and function between humans and other species.

Patients with fragile X syndrome show mental retardation, behavioural abnormalities, facial anomalies and macroorchidism due to the lack of the FMR1 protein (FMRP). Recently a knockout mouse model for fragile X syndrome has been made through homologous recombination of the murine Fmr1 gene by an inactivated Fmr1 gene construct in embryonic stem cells. The knockout mouse lacks Fmrp and shows symptoms similar to those found in fragile X patients. To answer the question whether reintroduction of Fmrp can restore the normal phenotype a transgenic mouse was generated expressing human FMRP, The FMR1 transgene was under control of a CMV promoter to obtain ubiquitous FMRP expression. Transgenic mice were crossed with knockout mice to obtain a transgenic knockout mouse. The rescue mouse did express FMR1 protein, but did not show a reversal of the phenotype, most likely because the level of FMRP expressed from the transgene is inadequate or not time or cell specific.

Partially nephrectomized (NX) and sham-operated mice were biochemically and behaviourally compared, 10 days, 1 month and 1 year post-surgery. Plasma urea and creatinine concentrations were mildly increased in all NX groups, but creatinine clearance was significantly decreased, 10 days post-surgery only. NX mice showed lower body weights and reduced growth. Wire suspension and rotarod indicated unaffected motor functions, but NX mice did show reduced ambulation and swimming velocity, 10 days post-surgery. Hidden-platform water maze indicated a spatial learning impairment in NX mice, 10 days post-surgery, which could not be entirely reduced to motor incapacity. The acute behavioural deficits in these mildly uremic mice may relate to analogous symptoms in uraernic encephalopathy, a poorly understood brain syndrome occurring in uraernic patients.

Guanidine, creatinine (CTN), methylguanidine (MG) and guanidinosuccinic acid (GSA) are four endogenous guanidino compounds with proven neuroexcitatory actions, and putative pathophysiological significance as uraemic toxins. The effects of these uraemic guanidino compounds, were studied on whole-cell current evoked by γ-amino butyric acid (GABA) on mouse spinal cord neurones in vitro. CTN, MG and GSA concentration dependently blocked GABA-evoked current with calculated IC50values (± SE) of 9.6±0.9, 9.7±1.5 and 5.1±0.4 mM, respectively. CTN, MG and GSA were shown to block inward and outward currents to the same extent, demonstrating voltage independent block of GABA-evoked current by these compounds. Guanidine, however, evoked inward whole-cell currents, which were almost completely blocked by strychnine, indicating that the guanidine-evoked current might have been due to glycine receptor activation.

A series of five experiments was conducted to investigate the temporal aspects of human memory consolidation of symbolic material through the administration of amphetamine. Subjects had to recall or recognise unrelated words from a previously presented list. The first experiments support the conjecture, based on animal studies, that amphetamine enhances long-term memory performance. Subsequently, enhancement is demonstrated with oral administration before learning, as well as with intramuscular injection after learning. It is shown that improved recall cannot be explained solely by general arousal or attentional processes, but must be due to consolidation. By introducing different test delays we show that consolidation of symbolic material can be modulated by amphetamine during the 1st hour after learning. In a final experiment we demonstrate that the memory enhancement applies to recall as well as to recognition. The implications of the present results are discussed in the context of recent research on LTP processes.

The neural cell adhesion molecule L1 (L1CAM) plays a key role during embryonic development of the nervous system and is involved in memory and learning. Mutations in the L1 gene are responsible for four X linked neurological conditions: X linked hydrocephalus (HSAS), MASA syndrome, complicated spastic paraplegia type 1 (SP-1), and X linked agenesis of the corpus callosum. As the clinical picture of these four L1 associated diseases shows considerable overlap and is characterised by Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia, and Hydrocephalus, these conditions have recently been lumped together into the CRASH syndrome. We investigate here whether a genotype-phenotype correlation exists in CRASH syndrome since its clinical spectrum is highly variable and numerous L1 mutations have been described. We found that (1) mutations in the extracellular part of L1 leading to truncation or absence of L1 cause a severe phenotype, (2) mutations in the cytoplasmic domain of L1 give rise to a milder phenotype than extracellular mutations, and (3) extracellular missense mutations affecting amino acids situated on the surface of a domain cause a milder phenotype than those affecting amino acids buried in the core of the domain.

Cholecystokinin (CCK) containing particles were isolated from rat striatum. After differential and isopycnic sucrose density gradient centrifugation, CCK containing particles equilibrated around 1.2 m sucrose. Dopamine (DA) containing particles equilibrated around the same buoyant density, but the colocalization of a cytosolic as well as a mitochondrial enzyme marker and the low enrichement at this density indicated an incomplete isolation of CCK containing particles from other subcellular organelles. Alternatively, differential centrifugation and gel filtration on Sephacryl S-1000 did yield advanced isolation of CCK containing vesicles. These vesicles also contain particle-bound DA. During hypo-osmotic lysis, these CCK and/or DA containing particles behaved like synaptic vesicles. Therefore, it was concluded that CCK containing vesicles from rat corpus striatum were indeed isolated and characterized and that the same or similar vesicles contain DA as well as CCK.

Fmr1 knockout mice constitute a putative model of fragile X syndrome, the most common form of heritable mental disability in humans. We have compared the performance of transgenic mice with anFmr1 knockout with that of normal littermates in hidden- and visible-platform water maze learning, and showed that knockouts exhibit subnormal spatial learning abilities and marginal motor performance deficits. During 12 training trials of the hidden-platform task, escape latency and path length decreased significantly in knockouts and control littermates, and no effect of genotype was found. During four ensuing reversal trials, however, significant differences were found between knockouts and control littermates both in escape latency and path length. During the visible-platform condition, the reversal trials also revealed a difference between knockouts and normal littermates in escape latency, but not in path length. Possibly due to marginal motor incapacity, knockouts swam significantly slower than controls during these latter trials. During both probe trials of the hidden-platform task, knockouts as well as normal littermates spent more time in the target quadrant than in the other quadrants, and percent of time spent in the target quadrant was the same in both groups; swimming velocity was not significantly different between knockouts and normal littermates during these trials. Entries in the target area during the probe trials did show a significant effect of genotype on number of entries.

CGP 40116 is the active (R)‐enantiomer of the most potent N‐methyl‐d‐aspartic acid (NMDA) receptor antagonist presently available: 2‐amino‐4‐methyl‐5‐phosphono‐3‐pentenoic acid (CGP 37849). In this study, we describe the effect of CGP 40116 on whole‐cell currents induced by excitatory amino acids in cultured mouse spinal cord cells by use of the whole‐cell patch‐clamp technique.We found that application of CGP 40116 in the nmrange, concentration‐dependently inhibited whole‐cell current evoked by 20 μmNMDA in mouse cultured spinal neurones (IC50±s.e.mean 48±8 nmCGP 40116).The compound appeared to be highly selective for the NMDA current. At concentrations as high 1 μm, currents evoked by α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) or kainic acid were not affected by CGP 40116. The threshold concentration for antagonism of NMDA‐induced responses was 10 nmsuggesting a selectivity ratio of 100 fold for NMDA receptors versus AMPA or kainate receptors.CGP 40116 produced a parallel rightward displacement of the NMDA log concentration‐current curve indicating competitive antagonism at the transmitter recognition site of the NMDA receptor complex. An apparent dissociation constant for the antagonist was calculated from the displacement of the agonist concentration‐current curve: 117±53 nmCGP 40116 (estimated Kd±s.e.). Like other competitive NMDA antagonists, CGP 40116 blocked NMDA‐evoked current in a voltage‐independent manner.

Glycine was intravenously injected in rabbits and resulted in a dose dependent hyperglycinemia. A dose of 10mmol/kg was sufficient to achieve plasma levels of 10 to 16mM comparable to serum levels in patients at the end of a transurethral prostatectomy. The experiments documented that hyperglycinemia is associated with a significant increase of this substance in tissues outside the plasma compartment. Glycine loading resulted in a tenfold elevation of this amino acid in cerebrospinal fluid 10 minutes after injection. In retina and vitreous humor a five- to tenfold increase in glycine content was observed at 10 minutes post injection while in the anterior chamber fluid the maximum increase appeared at 30 minutes.

Neuropsychiatric lupus (NPSLE) refers to the neurological and psychiatric manifestations that are commonly observed in patients with systemic lupus erythematosus (SLE). An important question regarding the pathogenesis of NPSLE is whether the symptoms are caused primarily by CNS-intrinsic mechanisms or develop as a consequence of systemic autoimmunity. Currently used spontaneous mouse models for SLE have already contributed significantly to unraveling how systemic immunity affects the CNS. However, they are less suited when interested in CNS primary mechanisms. In addition, none of these models are based on genes that are associated with SLE. In this study, we evaluate the influence of A20, a well-known susceptibility locus for SLE, on behavior and CNS-associated changes in inflammatory markers. Furthermore, given the importance of environmental triggers for disease onset and progression, the influence of an acute immunological challenge was evaluated.

Correction to: Molecular Psychiatry advance online publication, 2 December 2014; doi:10.1038/mp.2014.151 Following publication of this paper, the authors noticed that the eighth author’s name was misspelled. The author’s name should have been listed as E Marciniak.

No abstract