The effect of genetic background on behavioral manifestation of Grid2(Lc) mutation.

Mutant mice are commonly used models of hereditary diseases. Nevertheless, these mice have phenotypic traits of the original strain, which could interfere with the manifestation of the mutation of interest. Lurcher mice represent a model of olivocerebellar degeneration, which is caused by the Grid2(Lc) mutation. Lurchers show ataxia and various cognitive and behavioral abnormalities. The most commonly used strains of Lurcher mice are B6CBA and C3H, but there is no information about the role of genetic background on the Grid2(Lc) manifestation. The aim of this work was to compare spatial navigation in the Morris water maze, spontaneous activity in the open field and motor skills on the horizontal wire, slanted ladder and rotarod in B6CBA and C3H Lurcher mutant and wild type mice. The study showed impaired motor skills and water maze performance in both strains of Lurcher mice. Both C3H Lurcher and C3H wild type mice had poorer performances in the water maze task than their B6CBA counterparts. In the open field test, C3H mice showed higher activity and lower thigmotaxis. The study showed that genetic backgrounds can modify manifestations of the Lurcher mutation. In this case, B6CBA Lurcher mice models probably have more validity when studying the behavioral aspects of cerebellar degeneration than C3H Lurcher mice, since they do not combine abnormalities related to the Grid2(Lc) mutation with strain-specific problems.

The Roman High- and Low-Avoidance rat strains differ in fearpotentiated startle and classical aversive conditioning / Las cepas de ratas Roman de alta y baja evitación difieren en respuesta de sobresalto potenciada por miedo y en condicionamiento clásico aversivo

The Swiss sublines of Roman High-(RHA/Verh) and Low-(RLA/Verh) Avoidance rats have been genetically selected (and outbred) since 1972 because of their good versus extremely poor acquisition of two-way, active avoidance. Inbred strains (RHA-I and RLA-I), derived from those two lines, have been maintained at our laboratory since 1997. The RLA line/strain shows increased stress-induced endocrine responses and enhanced anxiety/fearfulness in a variety of unconditioned behavioural variables and tests. Thus far, however, the Roman rat strains have not been compared in procedures involving classical fear conditioning to cues or contexts. Therefore, the present work was aimed at comparing RHA-I and RLA-I rats in 1) two different procedures of fear-potentiated startle and 2) in a classical fear conditioning (i.e., conditioned freezing) paradigm. The results indicate that, compared to RHA-I rats, RLA-I animals display higher levels of conditioned fear (as measured either by startle responses or freezing behavior) across those different tasks (AU)

Las sublíneas suizas de ratas Romanas «High»-(RHA/Verh) y «Low»-(RLA/Verh) «Avoidance» han sido seleccionadas genéticamente, desde 1972, en función de su excelente (RHA) o extremadamente pobre adquisición de la tarea de evitación activa en dos sentidos. Cepas consanguíneas (RHA-I y RLA-I), derivadas de las dos líneas anteriores, se mantienen en nuestro laboratorio desde 1997. En comparación con la cepa RHA-I, la cepa RLA-I muestra incrementos en las respuestas hormonales al estrés, así como en conductas de ansiedad/miedo en una variedad de pruebas y variables conductuales incondicionadas. Hasta la fecha, las cepas de ratas Romanas no han sido comparadas en procedimientos de condicionamiento clásico de miedo a contextos o estímulos discretos. El presente trabajo tuvo como objetivo comparar ambas en 1) dos procedimientos de medida de la respuesta de sobresalto potenciada por miedo; y, 2) en un procedimiento de condicionamiento clásico de miedo (petrificación condicionada). Los resultados indican que las ratas RLA-I muestran niveles mayores de condicionamiento de miedo (respuesta de sobresalto y respuesta e petrificación) que las RHA-I, reforzando así los perfiles diferenciales de ansiedad/miedo de las dos cepas (AU)

Gene-environment interaction during early development in the heterozygous reeler mouse: clues for modelling of major neurobehavioral syndromes.

Autism and schizophrenia are multifactorial disorders with increasing prevalence in the young population. Among candidate molecules, reelin (RELN) is a protein of the extracellular matrix playing a key role in brain development and synaptic plasticity. The heterozygous (HZ) reeler mouse provides a model for studying the role of reelin deficiency for the onset of these syndromes. We investigated whether early indices of neurobehavioral disorders can be identified in the infant reeler, and whether the consequences of ontogenetic adverse experiences may question or support the suitability of this model. A first study focused on the link between early exposure to Chlorpyryfos and its enduring neurobehavioral consequences. Our data are interesting in view of recently discovered cholinergic abnormalities in autism and schizophrenia, and may suggest new avenues for early pharmacological intervention. In a second study, we analyzed the consequences of repeated maternal separation early in ontogeny. The results provide evidence of how unusual stress early in development are converted into altered behavior in some, but not all, individuals depending on gender and genetic background. A third study aimed to verify the reliability of the model at critical age windows. Data suggest reduced anxiety, increased impulsivity and disinhibition, and altered pain threshold in response to morphine for HZ, supporting a differential organization of brain dopaminergic, serotonergic and opioid systems in this genotype. In conclusion, HZ exhibited a complex behavioral and psycho-pharmacological phenotype, and differential responsivity to ontogenetic adverse conditions. HZ may be used to disentangle interactions between genetic vulnerability and environmental factors. Such an approach could help to model the pathogenesis of neurodevelopmental psychiatric diseases.

Assessment of cognitive function in the heterozygous reeler mouse.

RATIONALE: The heterozygous reeler mouse has been proposed as a genetic mouse model of schizophrenia based on several neuroanatomical and behavioral similarities between these mice and patients with schizophrenia. However, the effect of reelin haploinsufficiency on one of the cardinal symptoms of schizophrenia, the impairment of prefrontal-cortex-dependent cognitive function, has yet to be determined. OBJECTIVE: Here, we investigated multiple aspects of cognitive function in heterozygous reeler mice that are known to be impaired in schizophrenic patients. METHODS: Heterozygous reeler mice were assessed for (1) cognitive flexibility in an instrumental reversal learning task, (2) impulsivity in an inhibitory control task, (3) attentional function in a three-choice serial reaction time task, and (4) working memory in a delayed matching-to-position task. RESULTS: No differences were found between heterozygous reeler mice and wild-type littermate controls in any prefrontal-related cognitive measures. However, heterozygous reeler mice showed deficits in the acquisition of two operant tasks, consistent with a role for reelin in certain forms of learning. CONCLUSIONS: These findings suggest that heterozygous reeler mice may not be an appropriate model for the core prefrontal-dependent cognitive deficits observed in schizophrenia, but may model more general learning deficits that are associated with many psychiatric disorders.

Effect of training on motor abilities of heterozygous staggerer mutant (Rora(+)/Rora(sg)) mice during aging.

Heterozygous cerebellar mutant (Rora(+)/Rora(sg)) mice and control (Rora(+)/Rora(+)) mice of the same C57Bl6/J strain, 3-24 months old, were subjected to motor training on a rotorod for 10 days. Falling latency and percentage of time spent walking were measured. A good correlation was found between falling latency and walking time: the mice which maintained equilibrium for a long time were those which were walking, and the mice which fell early were those which were gripping suggesting that walking is obviously the most adapted strategy to keep balance on the rotorod. In Rora(+)/Rora(+) mice, scores before training were altered very precociously (from 6 months of age). Moreover, scores of Rora(+)/Rora(sg) mice were lower than those of Rora(+)/Rora(+) mice from the age of 3 months, while neuronal number in the cerebellar cortex of these mutants was quite normal and similar to that of Rora(+)/Rora(+) mice. This suggests that the motor skill disability would be due to fine structural and/or biochemical changes preceding neuronal death. Such subtle changes would begin several months earlier in Rora(+)/Rora(sg) than in Rora(+)/Rora(+) mice. Training on the rotorod resulted in increased scores in both genotypes at all ages. Motor learning abilities were therefore preserved in animals with a moderate neuronal loss in the cerebellum. It may be that motor learning is partly compensated by the striatum, which is known to play a major role in learning of motor skills.

Reactivity to object and spatial novelty is normal in older Ts65Dn mice that model Down syndrome and Alzheimer's disease.

Ts65Dn mice, a model for Down syndrome and Alzheimer's disease, have a spontaneous age-related reduction of cholinergic markers in medial septal neurons, hippocampal abnormalities, and an age-related learning deficit in a task that requires an intact hippocampus. Others have shown that when normal rodents explored an open field with objects, they detected the displacement of some of the familiar objects within the arena (spatial novelty) and the presence of a new object (object novelty); whereas rodents with hippocampal, fornix, or neonatal selective basal forebrain cholinergic lesions were impaired in detecting spatial, but not object, novelty. In this study, both control and Ts65Dn mice responded to both the spatial and object changes. This unexpected finding could have several explanations. One may be related to recent studies that suggest that only rats with neonatal, but not adult, basal forebrain cholinergic 192 IgG-saporin lesions are impaired in reacting to spatial novelty.

The development of behavioral abnormalities in the motor neuron degeneration (mnd) mouse.

The motor neuron degeneration (mnd) mouse, which has widespread abnormal accumulating lipoprotein and neuronal degeneration, has a mutation in CLN8, the gene for human progressive epilepsy with mental retardation (EPMR). EPMR is one of the neuronal ceroid lipofuscinoses (NCLs), a group of neurological disorders characterized by autofluorescent lipopigment accumulation, blindness, seizures, motor deterioration, and dementia. The human phenotype of EPMR suggests that, in addition to the motor symptoms previously categorized, various types of progressive behavioral abnormalities would be expected in mnd mice. We have therefore examined exploratory behavior, fear conditioning, and aggression in 2-3 month and 4-5 month old male mnd mice and age-matched C57BL/6 (B6) controls. The mnd mice displayed increased activity with decreased habituation in the activity monitor, poor contextual and cued memory, and heightened aggression relative to B6 controls. These behavioral deficits were most prominent at 4-5 months of age, which is prior to the onset of gross motor symptoms at 6 months. Our results provide a link from the mutation via pathology to a quantifiable multidimensional behavioral phenotype of this naturally occurring mouse model of NCL.

The heterozygote reeler mouse as a model for the development of a new generation of antipsychotics.

Neurochemical and structural prefrontal cortex abnormalities, including decreased reelin and glutamic acid decarboxylase (GAD)(67) expression, decreased thickness, increased neuronal packing density and decreased neuropil and dendritic spine number, are characteristics of schizophrenia neuropathology. Reelin is an extracellular matrix protein secreted by GABAergic interneurons that, acting through pyramidal neuron integrin receptors, provides a signal for dendritic spine plasticity. Heterozygous reeler mice that exhibit a 50% downregulation of reelin expression (mRNA and protein) replicate the dendritic spine and GABAergic defects described in schizophrenia. This genetic mouse model may be of value to reveal those GABAergic and integrin receptor signal transduction mechanisms that are likely to be downregulated by reelin deficiency in the brain of schizophrenia patients. An understanding of the epigenetic regulation of reelin gene expression and of the possible pathogenetic role of reelin deficiency in schizophrenia, may become a major focus that will open new avenues for the treatment of this disease.

The effects of the lurcher mutation on object localization, T-maze discrimination, and radial arm maze tasks.

The Lurcher mutation is characterized by degeneration of the cerebellar cortex and cerebellar ataxia. The mutants were compared to littermate controls of the same background strain in three spatial tasks: 1) left-right discrimination in a water-filled T-maze, a reference memory task requiring a win-stay strategy; 2) the radial arm maze, a working memory task requiring a win-shift strategy; 3) object localization, a reference memory task requiring the use of cognitive mapping. Lurcher mutants were impaired in the object localization and radial arm maze tasks but not in the left-right discrimination task. These results indicate that trial-independent tasks and reference memory tasks using cognitive mapping may be particularly vulnerable to cerebellar degeneration.

Coloboma mouse mutant as an animal model of hyperkinesis and attention deficit hyperactivity disorder.

Hyperkinesis and developmental behavioral deficiencies are cardinal signs of attention-deficit hyperactivity disorder. In mice, the mutation coloboma (Cm) corresponds to a contiguous gene defect that results in phenotypic abnormalities including spontaneous hyperactivity, head-bobbing, and ocular dysmorphology. In addition, coloboma mutant mice exhibit delays in achieving complex neonatal motor abilities and deficits in hippocampal physiology, which may contribute to learning deficiencies. The hyperkinesis is ameliorated by low doses of the psychostimulant D-amphetamine and can be rescued genetically by a transgene encoding SNAP-25, located within the Cm deletion. Together with syntaxin and synaptobrevin/VAMP, SNAP-25 constitutes a core protein complex integral to synaptic vesicle fusion and neurotransmitter release. Despite the ubiquitous role of SNAP-25 in synaptic transmission, and uniformly decreased expression in the mutants, coloboma mice show marked deficits in Ca2+-dependent dopamine release selectively in dorsal but not ventral striatum. This suggests that haploinsufficiency of SNAP-25 reveals a specific vulnerability of the nigrostriatal pathway which regulates motor activity and may provide a model for impaired striatal input into executive functions encoded by the prefrontal cortex associated with ADHD.

Comparison of the behavior of the curly tail and CBA mouse on a neurologic scale.

ct/ct mice are a mutation of the CBA strain with a high incidence of spina bifida (SB). Because humans with SB can exhibit abnormal behavior, we compared ct/ct and CBA mice using a neurologic assessment tool. ct/ct mice are more active and engage in more climbing, and stereotypical and compulsive behavior. When stimulated during cage removal ct/ct mice react more vigorously. ct/ct mice react more vigorously to a novel stimulus, and will vigorously search for a stable surface during visual placement. In the open field ct/ct mice crossed more lines and reared more than CBA. ct/ct mice demonstrated deficient performance in a modified Morris water maze. No differences were noted for other behaviors tested. The results argue that the mutation that produces SB in ct/ct mice also alters brain structure or chemistry. This is consistent with the findings in humans where SB can produce a variety of behavioral anomalies, most notably hyperactivity, attentional disorders, learning disabilities, and developmental lags.

Impaired short- and long-term memory in Ts65Dn mice, a model for Down syndrome.

Ts65Dn (TS), control littermates (CO) and Swiss (SW) male mice were tested in the elevated plus-maze and in the Morris water maze (MWM) for memory evaluation. In the plus-maze, each mouse was placed at the end of an open arm and initial freezing and the time to enter into an enclosed arm (transfer latency) were measured. SW mice decreased both measures over repeated trials, whereas no decrease of freezing was observed in CO mice, thus suggesting increased emotionality in this group. Compared to CO mice, TS mice showed less initial freezing, shorter transfer latencies, and spent less time in enclosed arms, suggesting a reduced ability to habituate or to inhibit behaviour. Animals were also submitted to a learning-set paradigm consisting of reaching a new platform position each day in the MWM. Two training phases (separated by a resting period of 6 weeks), each including eight acquisition and four cued sessions, were performed (each session consisting of four pairs of trials). CO and SW mice already reached an asymptotic performance by the second day of the first phase whereas TS mice did not achieve that level until the second training phase. The progression over trials indicated that CO and SW animals learned the new platform position between trials 1 and 2 of each session, whereas TS animals failed to do it and had more difficulties to find the platform when it was placed in the centre of the pool as compared to the other positions (SW, NE, E). The results suggest that TS mice show working memory impairments in addition to long-term memory deficits, although extensive training appeared to facilitate TS mice to achieve a level of performance similar to their control littermates. This represents another aspect of the cognitive deficits shown by TS mice: a mouse model of the human Down syndrome.

Learning and memory in the SAMP8 mouse.

The SAMP8 (P8) mouse strain develops deficits in learning and memory relatively early in its lifespan. This review provides an overview of the age-related changes that occur in P8 mice. Behavioral studies with P8 mice show impaired acquisition and retention as early as 4 months of age. Deficits in acquisition and retention occur with both aversive and appetitive training tasks. Anatomical studies have detected a number of age-related changes that occur in the central nervous system of P8 mice. The age-related increase in amyloid beta protein is well correlated with the age-related decline in learning and memory. Antibody to amyloid beta protein injected prior to training alleviated impaired acquisition and retention, whereas post-training injections alleviated retention deficits in older P8 mice. Biochemical studies have detected numerous age-related changes with reduced NMDA receptor activity most closely related to impaired learning and memory in P8 mice. Pharmacological studies have found age-related functional changes in the ability of drugs to improve memory processing in P8 mice in the septum and the hippocampus. The specific pattern of pharmacological changes and the inferred change in neurotransmitter activity suggest that age-related impairment in memory processing may be due to impaired septohippocampal interactions. The proposal that P8 mice may be a useful model for studying the early phases of age-related dementia of the Alzheimer type, while still requiring considerable study, seems reasonable.

Neocortical ectopias in BXSB mice: effects upon reference and working memory systems.

BXSB mice have an approximately 40-60% incidence of neocortical ectopias in layer I of the prefrontal/motor cortex. Prior studies have found major behavioral differences between those with ectopias and their non-ectopic littermates. Some of these findings indicate that the two groups differ with respect to spatial reference and working memory. The purpose of this study was to measure reference and working memory in the same animals to test the hypothesis that the ectopics would have better reference memory but less effective working memory. The Lashley III maze has cul-de-sacs which must be eliminated, and T-choices where the animal has to decide whether to go left or right. Ectopic and non-ectopic mice were equally able to learn the maze and did not differ on cul-entry or T-choice errors. Then the maze was inverted and the animals were retested. Turning the maze upside down did not change the relative status of the blind alleys. Therefore, the reference memory knowledge from the prior week's training could be used to avoid entering the culs. However, inverting the maze caused a left-right mirror image reversal of the T-choices. Therefore, prior reference memory information would interfere with learning the new path through the maze, whereas working memory would enable the mouse to eliminate T-choice errors. Ectopic mice made less cul-entry errors and more T-choice errors than their non-ectopic littermates, as predicted.

Behavior, cortical ectopias, and autoimmunity in BXSB-Yaa and BXSB-Yaa+ mice.

The BXSB-Yaa recombinant inbred strain was created by crossing a male SB/Le with a female C57BL/6J. A Y chromosome factor derived from the SB/Le male, known as the autoimmune accelerator (Yaa), leads to an earlier onset and greater severity of autoimmune disease in males. In contrast, male BXSB mice, which lack the Yaa gene (called BXSB-Yaa+) because their Y chromosome is derived from the C57BL/6J, do not develop an autoimmune condition. To examine the influence of the Y chromosome on behavior, cortical ectopia incidence, and immune functioning, males and females of these two strains were compared. Significant strain differences (for both sexes) were found for behavioral measures including discrimination, spatial and avoidance learning, and activity. For immunological parameters, a sex difference was seen in the BXSB-Yaa (males more autoimmune), but not in the BXSB-Yaa+ strain. As expected, male BXSB-Yaas were more autoimmune than male BXSB-Yaa+s. However, there was also a strain difference for IgG in the females (BXSB-Yaa+ greater). No strain difference was found for the presence of ectopias. However, there was a sex difference across both strains, with males having a higher incidence. BXSB-Yaa and BXSB-Yaa+ mice have behavioral and immunological differences greater than would be predicted by their known genetic differences. The significant differences between the two female groups suggest that the two strains differ with respect to autosomal genes, in addition to the Y chromosome. The incidence of ectopias is independent of this genetic difference and is influenced by the subject's sex.

The Lurcher cerebellar mutant phenotype is not expressed on a staggerer mutant background.

The hierarchy of the various processes responsible for the development of the complex, elaborated Purkinje cell can be examined by taking advantage of a series of spontaneous mutations that affect cerebellar development in the mouse. This study uses double mutants containing genes for two separate hereditary cerebellar mutations that have been shown to act intrinsically in Purkinje cells in order to investigate the time course and modes of action of these mutations. Lurcher mice show 100% degeneration of Purkinje cells, starting during the second postnatal week, while staggerer mice show reduced numbers of Purkinje cells in a distinctive mediolateral distribution from the time of birth, with the remainder grossly stunted. When these mutations are combined genetically, mice shown by progeny tests to harbor both staggerer and Lurcher genotypes exhibit staggerer-like behavior and overall cerebellar morphology; they also do not lose 100% of their Purkinje cells, as Lurcher mutants would otherwise do. Instead, they show a characteristic staggerer cerebellar pathology. We conclude that the intrinsic action of the staggerer gene in Purkinje cells occurs earlier in development than do effects of the Lurcher gene, and that the action of the staggerer gene prevents Purkinje cells from acquiring the characteristics required for the cytotoxic action of the Lurcher gene.