Arielle Ungerer

Behavioral disturbances in transgenic mice overexpressing the V717F β-amyloid precursor protein

PDAPP transgenic mice have been shown to develop age dependently much of the cerebral histopathology associated with Alzheimers disease. PDAPP mice (3-10 months old) were tested in a battery of memory tasks to determine whether they develop memory-behavioral deficits and whether these deficits occur before or after amyloid deposition. PDAPP mice manifest robust impairments in a radial-maze spatial discrimination task at all ages tested. Mild deficits were observed in a barpress learning task in 3-month-old PDAPP mice. In contrast, PDAPP mice show an age-dependent decrease in spontaneous object-recognition performance that appears to be severe at ages when amyloid deposition is known to occur. Thus, the PDAPP mouse shows severe deficits in the radial maze well before amyloid plaque deposition, whereas object-recognition performance decreases with age and may be associated with amyloid deposition.

Neuroanatomical Abnormalities in Behaviorally Characterized APPV717F Transgenic Mice

Histological analyses were performed on the brains of APP(V717F) transgenic (Tg)mice previously studied in a battery of behavioral tests. We describe here the regional and age-dependent deposition of amyloid in both heterozygous and homozygous Tg mice. We also report that Tg mice show significant and age-dependent changes in synaptic density measured by synaptophysin immunoreactivity. Surprisingly, a rather marked hippocampal atrophy is observed as early as 3 months of age in Tg mice (20-40%). Statistical analyses revealed that the deficits in object recognition memory are related to the number of amyloid deposits in specific brain regions, whereas deficits in spatial reference and working memory are related to the changes in synaptic density and hippocampal atrophy. Our study suggests that the behavioral deficits observed in Tg mice are only in part related to amyloid deposition, but are also related to neuroanatomical alterations secondary to overexpression of the APP(V717F) transgene and independent of amyloid deposition.

Involvement of sst2 somatostatin receptor in locomotor, exploratory activity and emotional reactivity in mice.

Somatostatin (SRIF) controls many physiological and pathological processes in the central nervous system but the respective roles of the five receptor isotypes (sst1–5) that mediate its effects are yet to be defined. In the present study, we attempted to identify functions of the sst2 receptor using mice with no functional copy of this gene (sst2 KO mice). In contrast with control 129Sv/C57Bl6 mice, sst2 mRNA was no longer detectable in the brain of sst2 KO mice; 125I‐labeled Tyr0DTrp8‐SRIF14 binding was also greatly reduced in almost all brain structures except for the hippocampal CA1 area, demonstrating that sst2 accounts for most SRIF binding in mouse brain. Invalidation of this subtype generated an increased anxiety‐related behaviour in a number of behavioural paradigms, while locomotor and exploratory activity was decreased in stress‐inducing situations. No major motor defects could be detected. sst2 KO mice also displayed increased release of pituitary ACTH, a main regulator of the stress response. Thus, somatostatin, via sst2 receptor isotype pathways, appears involved in the modulation of locomotor, exploratory and emotional reactivity in mice.

Influence of dystrophin-gene mutation on mdx mouse behavior. I. Retention deficits at long delays in spontaneous alternation and bar-pressing tasks.

X-linked Duchenne muscular dystrophy (DMD) is frequently associated with a nonprogressive, cognitive defect attributed to the absence of dystrophin in the brain of DMD patients. The mutantmdx mouse, lacking in 427-kDa dystrophin in both muscle and brain tissues, is considered to be a valuable model of human DMD. In the present study, we comparedmdx and C57BL/10 control mice and showed thatmdx mice had impaired retention in a T-maze, delayed spontaneous alternation task 24 h, but not 6 h, after acquisition.mdx mice were not impaired in acquisition of a bar-pressing task on 4 consecutive days but showed poor retention 22 days after the last training session. Mutants and controls showed similar behavioral responses in free exploration and light/dark choice situations and did not differ in spontaneous locomotor activity or motor coordination. Retention impairments at long delays inmdx mice suggest a role of dystrophin in long-term consolidation processes.

The neurosteroid pregnenolone sulfate reduces learning deficits induced by scopolamine and has promnestic effects in mice performing an appetitive learning task

The effects of the neurosteroid pregnenolone sulfate (PS) on learning as well as on scopolamine-induced learning deficits were studied in Swiss mice using an appetitively reinforced Go-No Go visual discrimination task. Subcutaneous (SC) administration of scopolamine (0.3–3 mg/kg) after the first session of training dose-dependently impairs learning during the following sessions in this task. Moreover, intracerebroventricular (ICV) administration of PS (0.01–10 nmol) dose-dependently blocks learning deficits induced by scopolamine (3 mg/kg), with the most potent effects at the dose of 0.5 nmol PS. In addition to antagonizing the amnestic effects of scopolamine, PS (0.5 nmol ICV) has a memory-enhancing effect, when administered alone after the first training session. Scopolamine (3 mg/kg SC) also produced substantial deficits on retrieval performance in the Go-No Go visual discrimination task, and caused motor disturbances, when administered 15 min before testing. PS (0.5 nmol ICV) also reduced scopolamine-induced deficits on retrieval but had no effect on scopolamine-induced motor impairments in the traction reflex test. Such a rapid effect of PS on memory processes may be mediated via NMDA and/or GABAA receptors.

Early regional cerebral glucose hypometabolism in transgenic mice overexpressing the V717F β-amyloid precursor protein

In the present study, we examined whether the relative levels of regional brain [14C]2-deoxyglucose (2-DG) uptake are altered in a transgenic mouse model of Alzheimers disease which overexpresses a mutated form of the human beta-amyloid precursor protein (mutation V717F). We show that the relative levels of 2-DG uptake are significantly reduced in the septum, thalamus, dentate gyrus and parietal cortex of 3-month-old transgenic mice as compared with wild-type littermates. In 10-month-old transgenic mice, these alterations also extend to the CA3 hippocampal region, the cingulate, retrosplenial, occipital and temporal cortices, suggesting an age-dependent decrease in the regional 2-DG uptake. These results suggest that expression of a mutated APP gene induces an early regional cerebral hypometabolism independently of amyloid deposition per se.

The beta-amyloid precursor protein and its derivatives: from biology to learning and memory processes.

Intensive investigation towards the understanding of the biology and physiological functions of the beta-amyloid precursor protein (APP) have been supported since it is known that a 39-43 amino acid fragment of APP, called the beta-amyloid protein (Abeta), accumulates in the brain parenchyma to form the typical lesions associated with Alzheimers disease (AD). It emerges from extensive data that APP and its derivatives show a wide range of contrasting physiological properties and therefore might be involved in distinct physiological functions. Abeta has been shown to disrupt neuronal activity and to demonstrate neurotoxic properties in a wide range of experimental procedures. In contrast, both in vitro and in vivo studies suggest that APP and/or its secreted forms are important factors involved in the viability, growth and morphological and functional plasticity of nerve cells. Furthermore, several recent studies suggest that APP and its derivatives have an important role in learning and memory processes. Memory impairments can be induced in animals by intracerebral treatment with Abeta. Altered expression of the APP gene in aged animals or in genetically-modified animals also leads to memory deficits. By contrast, secreted forms of APP have recently been shown to facilitate learning and memory processes in mice. These interesting findings open novel perspectives to understand the involvement of APP in the development of cognitive deficits associated with AD. In this review, we summarize the current data concerning the biology and the behavioral effects of APP and its derivatives which may be relevant to the roles of these proteins in memory and in AD pathology.

Spatial learning and synaptic hippocampal plasticity in type 2 somatostatin receptor knock-out mice.

Somatostatin is implicated in a number of physiological functions in the CNS. These effects are elicited through the activation of at least five receptor subtypes. Among them, sst2 receptors appear the most widely expressed in the cortex and hippocampal region. However, the specific role of this somatostatin receptor subtype in these regions is largely undetermined. In this study, we investigated the role of the sst2 receptor in the hippocampus using mice invalidated for the sst2 gene (sst2 KO mice). Complementary experimental approaches were used. First, mice were tested in behavioral tests to explore the consequences of the gene deletion on learning and memory. Spatial discrimination learning in the radial maze was facilitated in sst2 KO mice, while operant learning of a bar-pressing task was slightly altered. Mice were then processed for electrophysiological study using the ex vivo hippocampal slice preparation. Extracellular recordings in the CA1 area showed an enhancement in glutamatergic (AMPA and NMDA) responses in sst2 KO mice which displayed an increase in the magnitude of the short-term potentiation and long-term depression. In contrast, long-term potentiation was not significantly altered. Taken together, these data demonstrate that somatostatin, acting via sst2 hippocampal receptors, may contribute to a global decrease in glutamate efficiency and consequently alter glutamate-dependent plasticity and spatial learning.

The selective protein kinase C inhibitor, NPC 15437, induces specific deficits in memory retention in mice

We studied the effects of a selective inhibitor of protein kinase C (PKC), 2,6-diamino-N-[(1-(1-oxotridecyl)-2-piperidinyl]methyl)hexamide (NPC 15437), on acquisition and memory retention of a Y-maze avoidance task in mice. Post-training administration of NPC 15437 (0.1-10 mg/kg i.p.) induced a dose-dependent deficit in retention of the temporal but not the spatial component of the task. This selective amnesia does not reflect state dependence and NPC 15437 (1 mg/kg) had no effect on acquisition and memory retrieval. Our results suggest that this new PKC inhibitor interferes with mechanisms underlying memory consolidation. This is in agreement with recent findings suggesting that PKC is involved in memory processes.

Behavioral characterization of mdx3cv mice deficient in C-terminal dystrophins

Cognitive deficits are frequently associated with Duchenne muscular dystrophy (DMD). They might be due to a deficiency in the brain isoforms of the 427 kDa full-length dystrophin, and/or to altered expression of other C-terminal dystrophin-gene products (Dp71, Dp140) also found in brain. Mdx mice, which only lack full-length dystrophin in both muscle and brain, were previously shown to have moderate learning and memory deficits. In the present study, we investigated behavioral responses in mdx3cv mutants, which have altered expression of all the dystrophin-gene products. Contrary to the original mdx mice, mdx3cv mice showed enhanced anxiety-related behaviors and reduced locomotion as compared to control mice. Although those perturbations might be related to the lack in C-terminal dystrophins, they do not seem sufficient to induce strong learning deficits in this mutant. Indeed, we showed that mdx3cv mice may display similar or weaker deficits during the learning of a bar-pressing task, as compared to mdx mice. The relevance of the mdx3cv mutant as a model to study the cognitive deficits associated with DMD is discussed.