Biomedical subjects

David P Wolfer

Publications and source records attributed to David P Wolfer.

At least 19 recordsLinked to original sources

PubMed2006

Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories.

Arc/Arg3.1 is robustly induced by plasticity-producing stimulation and specifically targeted to stimulated synaptic areas. To investigate the role of Arc/Arg3.1 in synaptic plasticity and learning and memory, we generated Arc/Arg3.1 knockout mice. These animals fail to form long-lasting memories for implicit and explicit learning tasks, despite intact short-term memory. Moreover, they exhibit a biphasic alteration of hippocampal long-term potentiation in the dentate gyrus and area CA1 with an enhanced early and absent late phase. In addition, long-term depression is significantly impaired. Together, these results demonstrate a critical role for Arc/Arg3.1 in the consolidation of enduring synaptic plasticity and memory storage.

Analysis of Variance↗

PubMed2006

Neuronal neprilysin overexpression is associated with attenuation of Abeta-related spatial memory deficit.

Converging evidence links abnormally high brain concentrations of amyloid-beta peptides (Abeta) to the pathology of Alzheimer's disease (AD). Lowering brain Abeta levels, therefore, is a therapeutic strategy for the treatment of AD. Neuronal neprilysin upregulation led to increased degradation of Abeta, reduced the formation of Abeta-plaques and the associated cytopathology, but whether overexpression of neprilysin can improve cognition is unknown. We show that neuronal overexpression of neprilysin improved the Morris water maze memory performance in mice with memory deficits resulting from overexpression of the AD-causing mutated human amyloid precursor protein (APP). This improvement was associated with decreased brain levels of Abeta and with unchanged endoproteolytic processing of APP. These results provide the evidence that lowering of brain Abeta levels by increasing its degradation can improve cognitive functions in vivo, and suggest that increasing the activity of neprilysin in brain may be effective in preventing cognitive decline in AD.

Alzheimer Disease↗

PubMed2006

S100A1-deficient male mice exhibit increased exploratory activity and reduced anxiety-related responses.

S100 proteins comprise a family of Ca(2+) binding proteins of at least 21 members. They are distinctly expressed in a variety of cell types and tissues and are thought to play unique roles, although they share a high degree of sequence homology and expression overlap. S100A1 is prominently expressed in the heart, where it takes part in Ca(2+)-cycling. Its role in the central nervous system (CNS) is largely unknown. We have generated S100A1-deficient mice by gene trap mutagenesis to study the involvement of S100A1 in the cytoarchitecture of the brain, in learning and memory, and in avoidance-approach behavior. S100A1 knock out (KO) mice develop well and their brains present with normal morphology. In wild type (Wt) mice, S100A1 protein was found in the hippocampus, cerebral cortex and amygdala, and partially co-localized with the astrocyte marker glial fibrillary acidic protein (GFAP) in the stratum radiatum of the hippocampus. Astrocytes and neurons of S100A1KO mice did not differ from those of Wt mice regarding shape, distribution and density. In the water maze, S100A1KO mice performed equally well as Wt, implying that S100A1 is not involved in spatial learning and memory. In avoidance-approach tests, predominantly male S100A1KO mice showed reduced anxiety-like responses and enhanced explorative activities. We conclude that S100A1 plays a role in modulating innate fear and exploration of novel stimuli.

Animals↗

PubMed2006

Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration.

To investigate the consequences of inborn excessive erythrocytosis, we made use of our transgenic mouse line (tg6) that constitutively overexpresses erythropoietin (Epo) in a hypoxia-independent manner, thereby reaching hematocrit levels of up to 0.89. We detected expression of human Epo in the brain and, to a lesser extent, in the lung but not in the heart, kidney, or liver of tg6 mice. Although no acute cardiovascular complications are observed, tg6 animals have a reduced lifespan. Decreased swim performance was observed in 5-mo-old tg6 mice. At about 7 mo, several tg6 animals developed spastic contractions of the hindlimbs followed by paralysis. Morphological analysis by light and electron microscopy showed degenerative processes in liver and kidney characterized by increased vascular permeability, chronic progressive inflammation, hemosiderin deposition, and general vasodilatation. Moreover, most of the animals showed severe nerve fiber degeneration of the sciatic nerve, decreased number of neuromuscular junctions, and degeneration of skeletal muscle fibers. Most probably, the developing demyelinating neuropathy resulted in muscular degeneration demonstrated in the extensor digitorum longus muscle. Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy. This model allows investigation of the impact of excessive erythrocytosis in individuals suffering from polycythemia vera, chronic mountain sickness, or in subjects tempted to abuse Epo by means of gene doping.

Altitude Sickness↗

PubMed2006

Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo.

Accumulation of the beta-amyloid peptide (Abeta) in the brain is a major pathological hallmark of Alzheimer's disease (AD), leading to synaptic dysfunction, neuronal death, and memory impairment. The levels of neprilysin, a major Abeta-degrading enzyme, are decreased in AD brains and during aging. Because neprilysin cleaves Abeta in vivo, its down-regulation may contribute to the pathophysiology of AD. The aim of this study was to assess the consequences of neprilysin deficiency on accumulation of murine Abeta in brains and associated pathologies in vivo by investigating neprilysin-deficient mice on biochemical, morphological, and behavioral levels. Aged neprilysin-deficient mice expressed physiological amyloid precursor protein (APP) levels and exhibited elevated brain Abeta concentrations and amyloid-like deposits in addition to signs of neuronal degeneration in their brains. Behaviorally, neprilysin-deficient mice acquired a significantly weaker conditioned taste aversion that extinguished faster than the aversion of age-matched controls. Our data establish that, under physiological APP expression levels, neprilysin deficiency is associated with increased Abeta accumulation in the brain and leads to deposition of amyloid-like structures in vivo as well as with signs of AD-like pathology and with behavioral deficits.

Age Factors↗

PubMed2005

Loss of the limbic mineralocorticoid receptor impairs behavioral plasticity.

Corticosteroid action in the brain is mediated by the mineralocorticoid (MR) and the glucocorticoid (GR) receptor. Disturbances in MR- and GR-mediated effects are thought to impair cognition, behavior, and endocrine control. To assess the function of the limbic MR in these processes, we inactivated the MR gene in the forebrain of the mouse using the Cre/loxP-recombination system. We screened the mice with a limbic MR deficiency in various learning and exploration tests. The mutant mice show impaired learning of the water-maze task and deficits in measures of working memory on the radial maze due to behavioral perseverance and stereotypy. They exhibit a hyperreactivity toward a novel object but normal anxiety-like behavior. The behavioral changes are associated with abnormalities of the mossy fiber projection and an up-regulation of GR expression in the hippocampus. Adult mutant mice show normal corticosterone levels at circadian trough and peak. This genetic model provides important information about the consequences of a permanently altered balance between limbic MR and GR, with implications for stress-related neuroendocrine and neuropsychiatric diseases.

Animals↗

PubMed2005

Reduced locomotion in the serum and glucocorticoid inducible kinase 3 knock out mouse.

The serum and glucocorticoid inducible kinase isoform SGK3 is expressed in the brain including hippocampal neurons. It is activated by phosphoinositide-3 (PI3) kinase and thus a putative target of neurotrophic factors. In vitro experiments pointed to the ability of SGK3 to regulate several transporters and ion channels including the AMPA receptor GluR1. In order to explore the in vivo functional significance of SGK3 in the regulation of spatial learning and exploratory behavior, we assessed the performance of SGK3 knockout mice (SGK3-/-) and their wild type littermates (SGK3+/+) in a place navigation task in the water-maze, radial maze in a battery of forced and free exploration tests, acoustic startle and a test for motoric coordination. According to water-maze and radial maze testing reference and working memory was intact in SGK3-/- mice. However, detailed analysis of swimming patterns of SGK3-/- mice in the water-maze revealed a deficit in precision and goal-directed navigation in space. SGK3-/- mice showed reduced exploratory activity, which was observed in several environments and increased centre field avoidance in the open-field. SGK3-/- mice further showed reduced darting behavior on open surfaces, indicating that the knock out may modify basic patterns of locomotion. In conclusion, lack of SGK3 leads to subtle behavioral defects which may result from deranged neuronal regulation of transporters and ion channels.

Analysis of Variance↗

PubMed2005

Miniature neurologgers for flying pigeons: multichannel EEG and action and field potentials in combination with GPS recording.

To study the neurophysiology of large-scale spatial cognition, we analyzed the neuronal activity of navigating homing pigeons. This is not possible using conventional radio-telemetry suitable for short distances only. Therefore we developed a miniaturized data logger ("neurologger") that can be carried by a homing pigeon on its back, in conjunction with a micro-global position system (GPS) logger recording the spatial position of the bird. In its present state, the neurologger permits recording from up to eight single-ended or differential electrodes in a walking or flying pigeon. Inputs from eight independent channels are preamplified, band-pass filtered, and directed to an eight-channel, 10-bit analog-digital converter of the microcontroller storing data on a "Multimedia" or "Secure Digital" card. For electroencephalography (EEG), the logger permits simultaneous recordings of up to eight channels during maximally 47 h, depending on memory, while single unit activity from two channels can be stored over 9 h. The logger permits single unit separation from recorded multiunit signals. The neurologger with GPS represents a better alternative to telemetry that will eventually permit to record neuronal activity during cognitive and innate behavior of many species moving freely in their habitats but will also permit automated high-throughput screening of EEG in the laboratory.

Action Potentials↗

PubMed2005

Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease.

Mitochondrial dysfunction and oxidative stress have been implicated in Parkinson disease (PD). In addition, genetic evidence points to an important role of protein misfolding, aggregation, and failure in the proteasomal degradation of specific neuronal proteins in the pathogenesis of PD. The chaperone heat-shock protein 70 (Hsp70) reduces protein misfolding and aggregation and protects cells against a variety of adverse conditions, including oxidative stress. Moreover, Hsp70 exerts antiapoptotic activity by blocking the function of several key proapoptotic factors. Recently, Hsp70 was shown to inhibit alpha-synuclein toxicity in a Drosophila model of inherited PD. Here we tested the potential of Hsp70 (approved gene symbol HSPA1A) for gene therapy in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of idiopathic PD. We show that Hsp70 gene transfer to dopamine neurons by a recombinant adeno-associated virus significantly protects the mouse dopaminergic system against MPTP-induced dopamine neuron loss and the associated decline in striatal dopamine levels and tyrosine hydroxylase-positive fibers. Hsp70 reduced MPTP-induced apoptosis in the substantia nigra, and unilateral protection of the dopaminergic system by Hsp70 was associated with increased amphetamine-induced turning toward the uninjected side. Collectively, these results suggest that increasing chaperone activity may be beneficial for the treatment of idiopathic PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2004

Laboratory animal welfare: cage enrichment and mouse behaviour.

Mice housed in standard cages show impaired brain development, abnormal repetitive behaviours (stereotypies) and an anxious behavioural profile, all of which can be lessened by making the cage environment more stimulating. But concerns have been raised that enriched housing might disrupt standardization and so affect the precision and reproducibility of behavioural-test results (for example, see ref. 4). Here we show that environmental enrichment increases neither individual variability in behavioural tests nor the risk of obtaining conflicting data in replicate studies. Our findings indicate that the housing conditions of laboratory mice can be markedly improved without affecting the standardization of results.

Analysis of Variance↗

PubMed2004

Pigeon homing along highways and exits.

BACKGROUND: Anecdotal observations and early airplane and helicopter tracking studies suggest that pigeons sometimes follow large roads and use landmarks as turning points during their homeward journey. However, technical limitations in tracking pigeon routes have prevented proof. RESULTS: Here, we present experimental and statistical evidence for this strategy from the analysis of 216 GPS-recorded pigeon tracks over distances up to 50 km. Experienced pigeons released from familiar sites during 3 years around Rome, Italy, were significantly attracted to highways and a railway track running toward home, in many cases without anything forcing them to follow such guide-rails. Birds often broke off from the highways when these veered away from home, but many continued their flight along the highway until a major junction, even when the detour added substantially to their journey. The degree of road following increased with repeated releases but not flight length. Significant road following (in 40%-50% of the tracks) was mainly observed from release sites along northwest-southeast axis. CONCLUSIONS: Our data demonstrate the existence of a learned road-following homing strategy of pigeons and the use of particular topographical points for final navigation to the loft. Apparently, the better-directed early stages of the flight compensated the added final detour. During early and middle stages of the flight, following large and distinct roads is likely to reflect stabilization of a compass course rather than the presence of a mental roadmap. A cognitive (roadmap) component manifested by repeated crossing of preferred topographical points, including highway exits, is more likely when pigeons approach the loft area. However, it might only be expected in pigeons raised in an area characterized by navigationally relevant highway systems.

Animals↗

PubMed2004

The AP-1 transcription factor c-Jun is required for efficient axonal regeneration.

Nerve injury triggers numerous changes in the injured neurons and surrounding nonneuronal cells that ultimately result in successful target reinnervation or cell death. c-Jun is a component of the heterodimeric AP-1 transcription factor, and c-Jun is highly expressed in response to neuronal trauma. Here we have investigated the role of c-jun during axonal regeneration using mice lacking c-jun in the central nervous system. After transection of the facial nerve, the absence of c-Jun caused severe defects in several aspects of the axonal response, including perineuronal sprouting, lymphocyte recruitment, and microglial activation. c-Jun-deficient motorneurons were atrophic, resistant to axotomy-induced cell death, and showed reduced target muscle reinnervation. Expression of CD44, galanin, and alpha7beta1 integrin, molecules known to be involved in regeneration, was greatly impaired, suggesting a mechanism for c-Jun-mediated axonal growth. Taken together, our results identify c-Jun as an important regulator of axonal regeneration in the injured central nervous system.

Animals↗

PubMed2004

GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization.

Prostaglandin E2 (PGE2) is a crucial mediator of inflammatory pain sensitization. Here, we demonstrate that inhibition of a specific glycine receptor subtype (GlyR alpha3) by PGE2-induced receptor phosphorylation underlies central inflammatory pain sensitization. We show that GlyR alpha3 is distinctly expressed in superficial layers of the spinal cord dorsal horn. Mice deficient in GlyR alpha3 not only lack the inhibition of glycinergic neurotransmission by PGE2 seen in wild-type mice but also show a reduction in pain sensitization induced by spinal PGE2 injection or peripheral inflammation. Thus, GlyR alpha3 may provide a previously unrecognized molecular target in pain therapy.

Amino Acid Sequence↗

PubMed2004

Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1.

Rab proteins are small GTPases involved in intracellular trafficking. Among the 60 different Rab proteins described in mammals, Rab3a is the most abundant in brain, where it is involved in synaptic vesicle fusion and neurotransmitter release. Rab3a constitutive knockout mice (Rab3a(-/-)) are characterized by deficient short- and long-term synaptic plasticity in the mossy fiber pathway and altered circadian motor activity, while no effects on spatial learning have been reported so far for these mice. The goals of this study were to analyse possible behavioral consequences of the lack of synaptic plasticity in the mossy fiber pathway using a broad battery of sensitive behavioral measures that has been used previously to analyse the behavior of Gdi1 mice lacking a protein thought to regulate Rab3a. Rab3a(-/-) mice showed normal acquisition but moderately impaired platform reversal learning in the water maze including reference memory and episodic-like memory tasks. A mild deficit in spatial working memory was also observed when tested in the radial maze. Analysis of explorative behavior revealed increased locomotor activity and enhanced exploratory activity in open field, O-maze, dark/light box and novel object tests. Spontaneous activity in normal home cage settings was unaffected but Rab3a(-/-) mice showed increased motor activity when the home cage was equipped with a wheel. No differences were found for delayed and trace fear conditioning or for conditioned taste aversion learning. Congruent with earlier data, these results suggest that Rab3a-dependent synaptic plasticity might play a specific role in the reactivity to novel stimuli and behavioral stability rather than being involved in memory processing. On the other hand, the phenotypic changes in the Rab3a(-/-) mice bore no relation to the behavioral changes as observed in the Gdi1 mice. Such divergence in phenotypes implies that the putative synaptic interaction between Gdi1 and Rab3a should be reconsidered and re-analysed.

Animals↗

PubMed2003

Forebrain-specific trkB-receptor knockout mice: behaviorally more hyperactive than "depressive".

BACKGROUND: According to the neurotrophin hypothesis of depression, decreased activity of brain-derived neurotrophic factor (BDNF) contributes to behavioral and plasticity-related alterations in depressed patients. We investigated the hypothesis that mice with a forebrain-specific knockout of the trkB receptor, the main mediator of BDNF signaling, represent a genetic animal model for depression. METHODS: Using the CRE-loxP system, we bred trkB(CaMKII-CRE) mice with a trkB-receptor disruption in the forebrain. We subjected trkB-mutant mice to a battery of behavioral tests, comprising open field, elevated zero maze, emergence test, novel object test, and forced swim. Additionally, we investigated the hypothalamic-pituitary-adrenal (HPA) axis immunohistochemically and by plasma analyses. RESULTS: trkB(CaMKII-CRE) mice showed a stereotyped hyper-locomotion with reduced explorative activity, and impulsive reactions to novel stimuli. The trkB-mutant mice did not exhibit depressionlike behaviors such as increased "despair" in the forced swim test, increased anxiety in the elevated zero maze, or neophobia in the novel object test. Furthermore, no HPA dysregulation was observed under normal and stressful conditions. CONCLUSIONS: trkB(CaMKII-CRE) mice cannot be regarded as a genetic mouse model of depression. Instead, the behavioral symptoms of trkB(CaMKII-CRE) mice, comprising hyper-locomotion, stereotyped behaviors, and cognitive impairments, are similar to those postulated for mouse models of attention-deficit disorder.

Adrenocorticotropic Hormone↗

PubMed2003

Emotional instability but intact spatial cognition in adenosine receptor 1 knock out mice.

Several lines of evidence point to the involvement of adenosine in the regulation of important central mechanisms such as cognition, arousal, aggression and anxiety. In order to elucidate the involvement of the adenosine A1 receptor (A1AR) in spatial learning and the control of exploratory behaviour, we assessed A1AR knockout mice (A1AR-/-) and their wild-type littermates (A1AR+/+) in a place navigation task in the water maze and in a battery of forced and free exploration tests. In the water maze, A1AR-/- mice showed normal escape latencies and were indistinguishable from controls with respect to measures of spatial performance during both training and probe trial. But despite normal performance they showed increased wall hugging, most prominently after the relocation of the goal platform for reversal training. Quantitative analysis of strategy choices indicated that wall hugging was increased mainly at the expense of chaining and passive floating, whereas the frequency of trials characterised as direct swims or focal searching was normal in A1AR-/- mice. These results indicate intact spatial cognition, but mildly altered emotional reactions to the water maze environment. In line with this interpretation, A1AR-/- mice showed normal levels and patterns of activity, but a mild increase of some measures of anxiety in our battery of forced and free exploration paradigms. These results are in line with findings published using a genetically similar line, but demonstrate that the magnitude of the changes and the range of affected behavioural measures may vary considerably depending on the environmental conditions during testing.

Animals↗

PubMed2003

Does cAMP response element-binding protein have a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent memory?

Previous studies addressing the role of the transcription factor cAMP response element-binding protein (CREB) in mammalian long-term synaptic plasticity and memory by gene targeting were compromised by incomplete deletion of the CREB isoforms. Therefore, we generated conditional knock-out strains with a marked reduction or complete deletion of all CREB isoforms in the hippocampus. In these strains, no deficits could be detected in lasting forms of hippocampal long-term potentiation (LTP) and long-term depression (LTD). When tested for hippocampus-dependent learning, mutants showed normal context-dependent fear conditioning. Water maze learning was impaired during the early stages, but many mutants showed satisfactory scores in probe trials thought to measure hippocampus-dependent spatial memory. However, conditioned taste aversion learning, a putatively hippocampus-independent memory test, was markedly impaired. Our data indicate that in the adult mouse brain, loss of CREB neither prevents learning nor substantially affects performance in some hippocampus-dependent tasks. Furthermore, it spares LTP and LTD in paradigms that are sensitive enough to detect deficits in other mutants. This implies either a species-specific or regionally restricted role of CREB in the brain and/or a compensatory upregulation of the cAMP response element modulator (CREM) and other as yet unidentified transcription factors.

Animals↗

PubMed2003

Intact spatial memory in mice with seizure-induced partial loss of hippocampal pyramidal neurons.

We generated defined neuronal loss in hippocampus of genetically identical mice by pilocarpine injections and studied the impact of these seizures on the performance of mice in spatial learning and memory. The numbers of TUNEL-positive degenerating cells paralleled the severity of the seizures. When compared to the numbers found for not-seizured control mice, mild, moderate, and severe seizures produced significant increases in TUNEL-positive neurons in CA1 and CA3 regions by 19, 25, and 63%, respectively. Water maze learning was abolished after the severe seizures. However, spatial learning was normal after mild or moderate seizures. Therefore, there was no linear correlation between the impairment of learning and memory performance with the number of degenerating neurons in hippocampus. Our data suggest that normal spatial learning and memory can be achieved without the full number of hippocampal pyramidal neurons in partially lesioned hippocampus.

Animals↗