ABSTRACT
Planar cell polarity (PCP) signaling is well known to play a critical role during prenatal brain development; whether it plays specific roles at postnatal stages remains rather unknown. Here, we investigated the role of a key PCP-associated gene scrib in CA1 hippocampal structure and function at postnatal stages. We found that Scrib is required for learning and memory consolidation in the Morris water maze as well as synaptic maturation and NMDAR-dependent bidirectional plasticity. Furthermore, we unveiled a direct molecular interaction between Scrib and PP1/PP2A phosphatases whose levels were decreased in postsynaptic density of conditional knock-out mice. Remarkably, exposure to enriched environment (EE) preserved memory formation in CaMK-Scrib-/- mice by recovering synaptic plasticity and maturation. Thus, Scrib is required for synaptic function involved in memory formation and EE has beneficiary therapeutic effects. Our results demonstrate a distinct new role for a PCP-associated protein, beyond embryonic development, in cognitive functions during adulthood.
Subject(s)
Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/therapy , Environment , Intracellular Signaling Peptides and Proteins/deficiency , Neuronal Plasticity/physiology , Animals , COS Cells , Chlorocebus aethiops , Cognitive Dysfunction/pathology , Hippocampus/growth & development , Hippocampus/metabolism , Hippocampus/ultrastructure , Housing, Animal , Intracellular Signaling Peptides and Proteins/genetics , Learning Disabilities/pathology , Learning Disabilities/physiopathology , Learning Disabilities/therapy , Male , Memory Disorders/pathology , Memory Disorders/physiopathology , Memory Disorders/therapy , Mice, Knockout , Models, Molecular , Post-Synaptic Density/metabolism , Post-Synaptic Density/ultrastructure , Receptors, N-Methyl-D-Aspartate/metabolism , Synapses/metabolism , Synapses/ultrastructureABSTRACT
Arguably, one of the most important milestones in Huntington disease research since the discovery of the gene responsible has been the generation of different genetic animal models. Although clinical reports have shown evidence of progressive cognitive impairments in gene carriers before motor symptoms are diagnosed, such symptoms have been much less obvious in animal models. In this review, we summarize the three main classes of animal models for Huntington disease and describe some relevant translational assays for behavioural deficits evaluation. Finally, we argue that a good knowledge of the emergence of motor and cognitive symptoms in mice and rat models is indispensable for the selection of endpoint measures in early preclinical drug screening studies.
Subject(s)
Cognition Disorders/etiology , Disease Models, Animal , Huntington Disease/physiopathology , Animals , Cognition Disorders/genetics , Cognition Disorders/physiopathology , Drug Evaluation, Preclinical/methods , Endpoint Determination , Humans , Huntington Disease/genetics , Mice , Rats , Species Specificity , Translational Research, Biomedical/methodsABSTRACT
Chorea and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder, genetically characterized by the presence of expanded CAG repeats (>35) in the Huntingtin (HTT) gene. HD patients present psychiatric symptoms prior to the onset of motor symptoms and we recently found a similar emergence of non motor and motor deficits in BACHD rats carrying the human full length mutated HTT (97 CAG-CAA repeats). We evaluated cognitive performance in reversal learning and associative memory tests in different age cohorts of BACHD rats. Male wild type (WT) and transgenic (TG) rats between 2 and 12 months of age were tested. Learning and strategy shifting were assessed in a cross-maze test. Associative memory was evaluated in different fear conditioning paradigms (context, delay and trace). The possible confound of a fear conditioning phenotype by altered sensitivity to a 'painful' stimulus was assessed in a flinch-jump test. In the cross maze, 6 months old TG rats showed a mild impairment in reversal learning. In the fear conditioning tasks, 4, 6 and 12 months old TG rats showed a marked reduction in contextual fear conditioning. In addition, TG rats showed impaired delay conditioning (9 months) and trace fear conditioning (3 months). This phenotype was unlikely to be affected by a change in 'pain' sensitivity as WT and TG rats showed no difference in their threshold response in the flinch-jump test. Our results suggest that BACHD rats have a profound associative memory deficit and, possibly, a deficit in reversal learning as assessed in a cross maze task. The time course for the emergence of these symptoms (i.e., before the occurrence of motor symptoms) in this rat model for HD appears similar to the time course in patients. These data suggest that BACHD rats may be a useful model for preclinical drug discovery.
Subject(s)
Huntington Disease/psychology , Memory Disorders/psychology , Reversal Learning , Animals , Association Learning , Conditioning, Psychological , Disease Models, Animal , Fear , Female , Humans , Male , Maze Learning , Rats , Rats, Sprague-Dawley , Rats, Transgenic , Reaction TimeABSTRACT
RATIONALE: Huntington disease (HD) is frequently first diagnosed by the appearance of motor symptoms; the diagnosis is subsequently confirmed by the presence of expanded CAG repeats (> 35) in the HUNTINGTIN (HTT) gene. A BACHD rat model for HD carrying the human full length mutated HTT with 97 CAG-CAA repeats has been established recently. Behavioral phenotyping of BACHD rats will help to determine the validity of this model and its potential use in preclinical drug discovery studies. OBJECTIVES: The present study seeks to characterize the progressive emergence of motor, sensorimotor and cognitive deficits in BACHD rats. MATERIALS AND METHODS: Wild type and transgenic rats were tested from 1 till 12 months of age. Motor tests were selected to measure spontaneous locomotor activity (open field) and gait coordination. Sensorimotor gating was assessed in acoustic startle response paradigms and recognition memory was evaluated in an object recognition test. RESULTS: Transgenic rats showed hyperactivity at 1 month and hypoactivity starting at 4 months of age. Motor coordination imbalance in a Rotarod test was present at 2 months and gait abnormalities were seen in a Catwalk test at 12 months. Subtle sensorimotor changes were observed, whereas object recognition was unimpaired in BACHD rats up to 12 months of age. CONCLUSION: The current BACHD rat model recapitulates certain symptoms from HD patients, especially the marked motor deficits. A subtle neuropsychological phenotype was found and further studies are needed to fully address the sensorimotor phenotype and the potential use of BACHD rats for drug discovery purposes.
Subject(s)
Huntington Disease/physiopathology , Memory/physiology , Motor Activity/physiology , Recognition, Psychology/physiology , Sensory Gating/physiology , Animals , Behavior, Animal/physiology , Cognition Disorders/genetics , Cognition Disorders/metabolism , Cognition Disorders/physiopathology , Disease Models, Animal , Gait/physiology , Genotype , Humans , Huntingtin Protein , Huntington Disease/genetics , Huntington Disease/metabolism , Male , Motor Activity/genetics , Mutation , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Rats , Rats, Transgenic , Reflex, Startle/physiology , Rotarod Performance Test/methods , Sensory Gating/geneticsABSTRACT
RATIONALE: Huntington's disease (HD) is characterized by progressive motor dysfunction, emotional disturbances and cognitive deficits. It is a genetic disease caused by an elongation of the polyglutamine repeats in the huntingtin gene. Whereas HD is a complex disorder, previous studies in mice models have largely been confined to assessing motor deficits. OBJECTIVES: The aim of the present studies is a comprehensive phenotypical assessment of not only motor and gait deficits, but also of emotional and cognitive deficits in adult BACHD mice. MATERIAL AND METHODS: 46 male BACHD mice between 9 and 10 months of age were used. Wild type (+/+) and transgenic (+/T) mice were tested for motor deficits on a Rotarod and Catwalk system. Emotional deficits were assessed with the zero-maze and fear conditioning tests. Cognitive deficits in a strategy shifting task were evaluated in a cross-maze test. RESULTS: Comparing +/T and +/+ mice, we replicated the motor deficits in the transgenic mice that were previously described in the Rotarod test. For the first time, motor coordination imbalances in +/T animals are described in the Catwalk gait analysis system. +/T mice showed more anxiety-like behavior in the zero-maze test and a higher freezing response in the fear conditioning test. Reversal and strategy shifting impairments were demonstrated in the cross-maze, indicative of a disturbed prefrontal-striatal pathway. CONCLUSION: The results suggest that BACHD mice represent an animal model with a high degree of face validity for HD and may be very useful for testing novel therapeutic strategies.
