Susanna Pietropaolo

Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice.

Background No animal models of autism spectrum disorders (ASD) with good construct validity are currently available; using genetic models of pathologies characterized by ASD-like deficits, but with known causes, may be therefore a promising strategy. The Fmr1-KO mouse is an example of this approach, modeling Fragile X syndrome, a well-known genetic disorder presenting ASD symptoms. The Fmr1-KO is available on different genetic backgrounds (FVB versus C57BL/6), which may explain some of the conflicting results that have been obtained with these mutants up till now. Methods Fmr1 KO and their wild-type littermates on both the FVB and C57BL/6 genetic backgrounds were examined on a battery of tests modeling the clinical symptoms of ASD, including the triad of core symptoms (alterations in social interaction and communication, presence of repetitive behaviors), as well as the secondary symptoms (disturbances in sensori-motor reactivity and in circadian patterns of activity, epileptic events). Results Fmr1-KO mice displayed autistic-like core symptoms of altered social interaction and occurrence of repetitive behaviors with additional hyperactivity. The genetic background modulated the effects of the Fmr1 deletion and it appears that the C57BL/6 background may be more suitable for further research on core autistic-like symptoms. Conclusions The Fmr1-mouse line does not recapitulate all of the main core and secondary ASD symptoms, but still can be useful to elucidate the neurobiological mechanisms underlying specific ASD-like endophenotypes.

The role of voluntary exercise in enriched rearing: a behavioral analysis.

The effects of postweaning enriched rearing and home cage voluntary wheel-running exercise in adulthood were contrasted on a comprehensive battery of tests designed to assess mnemonic, attentional, emotional, and motor functions. In a 2 x 2 factorial design, female C57BL/6 mice were housed in groups in either standard or enriched cages, which were equipped with either a running or a locked wheel. They were maintained in the corresponding housing conditions for 2 months postweaning prior to, and throughout, testing. Enriched rearing was associated with anxiogenesis, hypolocomotor activity, enhanced motor skills, retarded extinction of conditioned responding, and improved water maze performance. Exercise as such enhanced motor coordination and facilitated extinction of contextual conditioning. Evidence for an interaction between enrichment and exercise was apparent in the open field test, conditioned freezing to a tone stimulus, prepulse inhibition, and acquisition of water maze reference memory. Hence, care should be taken to control for the unique contribution of wheel-running exercise when it is included as an integral component of the enrichment procedure.

The impact of voluntary exercise on mental health in rodents: a neuroplasticity perspective.

There is growing interest in the effects of voluntary wheel running activity on brain and behaviour in laboratory rodents and their implications to humans. Here, the major findings to date on the impact of exercise on mental health and diseases as well as the possible underlying neurobiological mechanisms are summarised. Several critical modulating factors on the neurobehavioural effects of wheel running exercise are emphasized and discussed--including the amount of wheel running, sex and strain/species differences. We also reported the outcome of an empirical investigation of the impact of wheel running exercise on the expression of both cognitive and non-cognitive phenotypes in a triple (3 x Tg-AD) transgenic mouse model for Alzheimers disease (AD). Clear sex- and paradigm-specific effects of exercise on the genetically determined phenotypes are illustrated, including the efficacy of wheel running activity in attenuating the sex-specific cognitive deficits. It is concluded that the wheel running paradigm represents a unique environmental manipulation for the investigation of neurobehavioural plasticity in terms of gene-environment interactions relevant to the pathogenesis and therapies of certain neuropsychiatric conditions.

Age-related accumulation of Reelin in amyloid-like deposits

Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimers disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Abeta species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD.

The expression of prepulse inhibition of the acoustic startle reflex as a function of three pulse stimulus intensities, three prepulse stimulus intensities, and three levels of startle responsiveness in C57BL6/J mice.

Using the acoustic startle reflex, prepulse inhibition (PPI) is typically demonstrated by the interaction between two auditory stimuli presented in close temporal proximity. When a startle-eliciting pulse stimulus is shortly preceded by a weak prepulse stimulus, the reaction to the former is attenuated in comparison to when the pulse stimulus is presented alone. The present experiment evaluated the influence of different prepulse and pulse intensities upon the expression of PPI by additionally taking into account individual differences in startle reactivity. To this end, we subdivided a cohort of 102 mice into three subsets of equal size differing in startle responsiveness, and evaluated PPI using three levels of prepulse stimulus in combination with three intensities of pulse stimulus. Our results revealed additive as well as complex interactive effects amongst individuals reactivity, pulse intensity and prepulse intensity. At the same time, additional issues concerning the quantification of PPI are highlighted, especially when startle reactivity differs considerably between comparison groups. We concluded that the variation in pulse intensity represents a valuable addition to PPI assessment in general, and especially in genetically modified mice.

The postweaning social isolation in C57BL/6 mice: preferential vulnerability in the male sex

IntroductionSocial deprivation during early life can severely affect mental health later in adulthood, leading to the development of behavioural traits associated with several major psychiatric disorders including schizophrenia. This has led to the application of social isolation in laboratory animals to model the impact of environmental factors on the aetiopathology of schizophrenia. However, controversy exists over the precise behavioural profile and the robustness of some of the reported effects of social isolation rearing.Materials and methodsHere, we evaluated the efficacy of postweaning social isolation to induce schizophrenia-related behavioural deficits in C57BL/6 mice of both sexes.ResultsThe effects of social isolation clearly differed between sexes: isolated male but not female mice exhibited multiple habituation deficits and enhanced locomotor reaction to amphetamine.DiscussionThe preferential vulnerability in the male sex corresponds well with the earlier disease onset and poorer prognosis in male relative to female schizophrenic patients. In contrast, we observed no evidence for a disruption of sensorimotor gating in the prepulse inhibition paradigm despite the efficacy of social isolation to alter startle reactivity. With both success and failure in the induction of schizophrenia-related endophenotypes, the present study thus provides important characterizations and qualifications to the application of the social isolation model in mice.ConclusionsWe conclude that social isolation in mice represents a valuable tool for the examination of candidate genes within the context of the “two-hit” hypothesis of the aetiological processes in schizophrenia.

Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1 −/y mice

Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1−/y mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.

Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease.

The triple-transgenic mouse line (3 x Tg-AD) harboring PS1M146V, APPSwe, and taup301L transgenes represents the only transgenic model for Alzheimers disease (AD) to date capturing both beta-amyloid and tau neuropathology. The present study provides an extensive behavioral characterization of the 3 x Tg-AD mouse line, evaluating the emergence of noncognitive and cognitive AD-like symptoms at two ages corresponding to the early (6-7 months) and advanced (12-13 months) stages of AD-pathology. Enhanced responsiveness to aversive stimulation was detected in mutant mice at both ages: the 3 x Tg-AD genotype enhanced acoustic startle response and facilitated performance in the cued-version of the water maze. These noncognitive phenotypes were accompanied by hyperactivity and reduced locomotor habituation in the open field at the older age. Signs of cognitive aberrations were also detected at both ages, but they were limited to associative learning. The present study suggests that this popular transgenic mouse model of AD has clear phenotypes beyond the cognitive domain, and their potential relationship to the cognitive phenotypes should be further explored.

Monogenic mouse models of social dysfunction: implications for autism.

Autism is a pervasive disorder characterized by a complex symptomatology, based principally on social dysfunction. The disorder has a highly complex, largely genetic etiology, involving an impressive variety of genes, the precise contributions of which still remain to be determined. For this reason, a reductionist approach to the study of autism has been proposed, employing monogenic animal models of social dysfunction, either by targeting a candidate gene, or by mimicking a single-gene disorder characterized by autistic symptoms. In the present review, we discuss this monogenic approach by comparing examples of each strategy: the mu opioid receptor knock-out (KO) mouse line, which targets the opioid system (known to be involved in the control of social behaviors); and the Fmr1-KO mouse, a model for Fragile X syndrome (a neurodevelopmental syndrome that includes autistic symptoms). The autistic-relevant behavioral phenotypes of the mu-opioid and Fmr1-KO mouse lines are described here, summarizing previous work by our research group and others, but also providing novel experimental evidence. Relevant factors influencing the validity of the two models, such as sex differences and age at testing, are also addressed, permitting an extensive evaluation of the advantages and limits of monogenic mouse models for autism.

Limited impact of social isolation on Alzheimer-like symptoms in a triple transgenic mouse model.

Gene-environment interactions are known to play a major role in the ethiopathology of several neuropsychiatric disorders, including Alzheimers disease (AD). The present study investigates whether environmental manipulations, that is, social isolation, may affect the genetic predisposition to develop AD-related traits in a triple transgenic mouse model (3 x Tg-AD), as suggested by our previous study employing physical exercise (Pietropaolo et al., 2008). Mutant and wild type mice of both sexes were housed singly or in groups from weaning, and evaluated behaviorally at 6 to 7 months of age. Independent of sex, the 3 x Tg-AD genotype was associated with enhanced acoustic startle response, improved performance in the cued version of the water maze and a clear impairment in the Y maze. Notably, the female (but not male) mutant mice showed increased anxiety. Although social isolation was effective in modifying several behaviors, it did not exacerbate any of the AD-like symptoms. Our findings demonstrated the differential susceptibility of the 3 x Tg-AD mouse line to environmental manipulations, showing that social isolation did not induce remarkable effects on the genetically determined AD-like symptoms, in contrast to what previously observed with physical exercise.