Chantal Mathis

PDE9A inhibition rescues amyloid beta-induced deficits in synaptic plasticity and cognition.

The cyclic nucleotide cGMP is an important intracellular messenger for synaptic plasticity and memory function in rodents. Therefore, inhibition of cGMP degrading phosphodiesterases, like PDE9A, has gained interest as potential target for treatment of cognition deficits in indications like Alzheimers disease (AD). In fact, PDE9A inhibition results in increased hippocampal long-term potentiation and exhibits procognitive effects in rodents. To date, however, no evidence has been published linking PDE9A inhibition to the pathologic hallmarks of AD such as amyloid beta (Aβ) deposition. Therefore, we investigated the role of PDE9A inhibition in an AD relevant context by testing its effects on Aβ-related deficits in synaptic plasticity and cognition. The PDE9A inhibitor BAY 73-6691 was found to restore long-term potentiation impaired by Aβ42 oligomers. Furthermore, we demonstrated that BAY 73-6691 enhanced cGMP levels in the hippocampus of APP transgenic tg2576 mice and improved memory performance of these mice. Altogether, our results support the hypothesis that inhibition of PDE9A could be a beneficial approach for the treatment of memory impairment in AD patients.

Detecting spatial memory deficits beyond blindness in tg2576 Alzheimer mice

The retinal degeneration Pde6b(rd1) (rd) mutation can be a major pitfall in behavioral studies using tg2576 mice bred on a B6:SJL genetic background, 1 of the most widely used models of Alzheimers disease. After a pilot study in wild type mice, performance of 8- and 16-month-old tg2576 mice were assessed in several behavioral tasks with the challenge of selecting 1 or more task(s) showing robust memory deficits on this genetic background. Water maze acquisition was impossible in rd homozygotes, whereas Y-maze alternation, object recognition, and olfactory discrimination were unaffected by both the transgene and the rd mutation. Spatial memory retention of 8- and 16-month-old tg2576 mice, however, was dramatically affected independently of the rd mutation when mice had to recognize a spatial configuration of objects or to perform the Barnes maze. Thus, the latter tasks appear extremely useful to evaluate spatial memory deficits and to test cognitive therapies in tg2576 mice and other mouse models bred on a background susceptible to visual impairment.

Attenuated behavioural responses to acute and chronic cocaine in GASP-1-deficient mice

G protein‐coupled receptor (GPCR) associated sorting protein 1 (GASP‐1) interacts with GPCRs and is implicated in their postendocytic sorting. Recently, GASP‐1 has been shown to regulate dopamine (D2) and cannabinoid (CB1) receptor signalling, suggesting that preventing GASP‐1 interaction with GPCRs might provide a means to limit the decrease in receptor signalling upon sustained agonist treatment. In order to test this hypothesis, we have generated and behaviourally characterized GASP‐1 knockout (KO) mice and have examined the consequences of the absence of GASP‐1 on chronic cocaine treatments. GASP‐1 KO and wild‐type (WT) mice were tested for sensitization to the locomotor effects of cocaine. Additional mice were trained to acquire intravenous self‐administration of cocaine on a fixed ratio 1 schedule of reinforcement, and the motivational value of cocaine was then assessed using a progressive ratio schedule of reinforcement. The dopamine and muscarinic receptor densities were quantitatively evaluated in the striatum of WT and KO mice tested for sensitization and self‐administration. Acute and sensitized cocaine‐locomotor effects were attenuated in KO mice. A decrease in the percentage of animals that acquired cocaine self‐administration was also observed in GASP‐1‐deficient mice, which was associated with pronounced down‐regulation of dopamine and muscarinic receptors in the striatum. These data indicate that GASP‐1 participates in acute and chronic behavioural responses induced by cocaine and are in agreement with a role of GASP‐1 in postendocytic sorting of GPCRs. However, in contrast to previous studies, our data suggest that upon sustained receptor stimulation GASP‐1 stimulates recycling rather than receptor degradation.

Touchscreen tasks in mice to demonstrate differences between hippocampal and striatal functions

In mammals, hippocampal and striatal regions are engaged in separable cognitive processes usually assessed through species-specific paradigms. To reconcile cognitive testing among species, translational advantages of the touchscreen-based automated method have been recently promoted. However, it remains undetermined whether similar neural substrates would be involved in such behavioral tasks both in humans and rodents. To address this question, the effects of hippocampal or dorso-striatal fiber-sparing lesions were first assessed in mice through a battery of tasks (experiment A) comprising the acquisition of two touchscreen paradigms, the Paired Associates Learning (dPAL) and Visuo-Motor Conditional Learning (VMCL) tasks, and a more classical T-maze alternation task. Additionally, we sought to determine whether post-acquisition hippocampal lesions would alter memory retrieval in the dPAL task (experiment B). Pre-training lesions of dorsal striatum caused major impairments in all paradigms. In contrast, pre-training hippocampal lesions disrupted the performance of animals trained in the T-maze assay, but spared the acquisition in touchscreen tasks. Nonetheless, post-training hippocampal lesions severely impacted the recall of the previously learned dPAL task. Altogether, our data show that, after having demonstrated their potential in genetically modified mice, touchscreens also reveal perfectly adapted to taxing functional implications of brain structures in mice by means of lesion approaches. Unlike its human counterpart requiring an intact hippocampus, the acquisition of the dPAL task requires the integrity of the dorsal striatum in mice. The hippocampus only later intervenes, when acquired information needs to be retrieved. Touchscreen assays may therefore be suited to study striatal- or hippocampal-dependent forms of learnings in mice.

ApoE4 confers better spatial memory than apoE3 in young adult hAPP-Yac/apoE-TR mice

The APOE-ɛ4 allele is associated with increased cognitive decline during normal aging and Alzheimers disease. However, several studies intriguingly found a beneficial effect on cognition in young adult human APOE-ɛ4 carriers. Here, we show that 3-month old bigenic hAPP-Yac/apoE4-TR mice outperformed their hAPP-Yac/apoE3-TR counterparts on learning and memory performances in the highly hippocampus-dependent, hidden-platform version of the Morris water maze task. The two mouse lines did not differ in a non-spatial visible-platform version of the task. This hAPP-Yac/apoE-TR model may thus provide a useful tool to study the mechanisms involved in the antagonistic pleiotropic effects of APOE-ɛ4 on cognitive functions.

Spatial Reference Memory is Associated with Modulation of Theta–Gamma Coupling in the Dentate Gyrus

Spatial reference memory in rodents represents a unique opportunity to study brain mechanisms responsible for encoding, storage and retrieval of a memory. Even though its reliance on hippocampal networks has long been established, the precise computations performed by different hippocampal subfields during spatial learning are still not clear. To study the evolution of electrophysiological activity in the CA1-dentate gyrus axis of the dorsal hippocampus over an iterative spatial learning paradigm, we recorded local field potentials in behaving mice using a newly designed appetitive version of the Barnes maze. We first showed that theta and gamma oscillations as well as theta-gamma coupling are differentially modulated in particular hippocampal subfields during the task. In addition, we show that dentate gyrus networks, but not CA1 networks, exhibit a transient learning-dependent increase in theta-gamma coupling specifically at the vicinity of the target area in the maze. In contrast to previous immediate early-gene studies, our results point to a long-lasting involvement of dentate networks in navigational memory in the Barnes maze. Based on these findings, we propose that theta-gamma coupling might represent a mechanism by which hippocampal areas compute relevant information.

Precocious Alterations of Brain Oscillatory Activity in Alzheimer’s Disease: A Window of Opportunity for Early Diagnosis and Treatment

Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia accounting for 50–80% of all age-related dementia. This pathology is characterized by the progressive and irreversible alteration of cognitive functions, such as memory, leading inexorably to the loss of autonomy for patients with AD. The pathology is linked with aging and occurs most commonly around 65 years old. Its prevalence (5% over 65 years of age and 20% after 80 years) constitutes an economic and social burden for AD patients and their family. At the present, there is still no cure for AD, actual treatments being moderately effective only in early stages of the pathology. A lot of efforts have been deployed with the aim of defining new AD biomarkers. Successful early detection of mild cognitive impairment (MCI) linked to AD requires the identification of biomarkers capable of distinguishing individuals with early stages of AD from other pathologies impacting cognition such as depression. In this article, we will review recent evidence suggesting that electroencephalographic (EEG) recordings, coupled with behavioral assessments, could be a useful approach and easily implementable for a precocious detection of AD.

Impaired striatum‐dependent behavior in GASP‐1‐knock‐out mice

G protein‐coupled receptor (GPCR) associated sorting protein‐1 (GASP‐1) is suspected to play a key role in recycling and degradation of several GPCRs. In a previous study, we have shown that GASP‐1‐knock‐out (GASP‐1‐KO) mice displayed deficits in acquiring a cocaine self‐administration task, associated with an exacerbated down‐regulation of striatal dopaminergic and cholinergic receptors. Among several possibilities, GASP‐1 deficiency could have impaired memory processes underlying the acquisition of the operant conditioning task. Therefore, the present study investigated cognitive performances of GASP‐1‐KO mice and their wild‐type littermates (WT) in a broad variety of memory tasks. Consistent with a deficit in procedural memory, GASP‐1‐KO mice showed delayed acquisition of a food‐reinforced bar‐press task. During water‐maze training in hidden‐ or visible‐platform paradigms, mutant and WT mice acquired the tasks at the same rate. However, GASP‐1 mice exhibited persistent thigmotaxic swimming, longer distance to the platform, and reduced swim speed. There was no deficit in several tasks requiring simple behavioral responses (Barnes maze, object recognition and passive avoidance tasks). Thus, the ability to acquire and/or express complex responses seems affected in GASP‐1‐deficient mice. Hippocampal functions were preserved, as the retention of an acquired memory in spatial tasks remained unaffected. The pattern of behavioral deficits observed in GASP‐1‐KO mice is coherent with current knowledge on the role of striatal GPCRs in acquisition/expression of skilled behavior and in motivation. Together with the previous findings, the so far established phenotype of GASP‐1‐KO mice makes them a potentially exciting tool to study striatal functions.

The Lateral Habenula as a Relay of Cortical Information to Process Working Memory

Abstract Working memory is a cognitive ability allowing the temporary storage of information to solve problems or adjust behavior. While working memory is known to mainly depend on the medial prefrontal cortex (mPFC), very few is known about how cortical information are relayed subcortically. By its connectivity, the lateral habenula (lHb) might act as a subcortical relay for cortical information. Indeed, the lHb receives inputs from several mPFC subregions, and recent findings suggest a role for the lHb in online processing of spatial information, a fundamental aspect of working memory. In rats, in a delayed non‐matching to position paradigm, using focal microinjections of the GABAA agonist muscimol we showed that inactivation of the lHb (16 ng in 0.2 &mgr;L per side), as well as disconnection between the prelimbic region of the mPFC (mPFC/PrL, 32 ng in 0.4 &mgr;L in one hemisphere) and the lHb (16 ng in 0.2 &mgr;L in the lHb in the contralateral hemisphere) impaired working memory. The deficits were unlikely to result from motivational or motor deficits as muscimol did not affect reward collection or cue responding latencies, and did not increase the number of omissions. These results show for the first time the implication of the lHb in mPFC‐dependent memory processes, likely as a relay of mPFC/PrL information. They also open new perspectives in the understanding of the top‐down processing of high‐level cognitive functions.

Defective response inhibition and collicular noradrenaline enrichment in mice with duplicated retinotopic map in the superior colliculus.

The superior colliculus is a hub for multisensory integration necessary for visuo-spatial orientation, control of gaze movements and attention. The multiple functions of the superior colliculus have prompted hypotheses about its involvement in neuropsychiatric conditions, but to date, this topic has not been addressed experimentally. We describe experiments on genetically modified mice, the Isl2-EphA3 knock-in line, that show a well-characterized duplication of the retino-collicular and cortico-collicular axonal projections leading to hyperstimulation of the superior colliculus. To explore the functional impact of collicular hyperstimulation, we compared the performance of homozygous knock-in, heterozygous knock-in and wild-type mice in several behavioral tasks requiring collicular activity. The light/dark box test and Go/No-Go conditioning task revealed that homozygous mutant mice exhibit defective response inhibition, a form of impulsivity. This defect was specific to attention as other tests showed no differences in visually driven behavior, motivation, visuo-spatial learning and sensorimotor abilities among the different groups of mice. Monoamine quantification and gene expression profiling demonstrated a specific enrichment of noradrenaline only in the superficial layers of the superior colliculus of Isl2-EphA3 knock-in mice, where the retinotopy is duplicated, whereas transcript levels of receptors, transporters and metabolic enzymes of the monoaminergic pathway were not affected. We demonstrate that the defect in response inhibition is a consequence of noradrenaline imbalance in the superficial layers of the superior colliculus caused by retinotopic map duplication. Our results suggest that structural abnormalities in the superior colliculus can cause defective response inhibition, a key feature of attention-deficit disorders.