Reversal of behavioural phenotype by the cannabinoid-like compound VSN16R in fragile X syndrome mice.

Fragile X syndrome is the most common inherited intellectual disability and mono-genetic cause of autism spectrum disorder. It is a neurodevelopmental condition occurring due to a CGG trinucleotide expansion in the FMR1 gene. Polymorphisms and variants in large-conductance calcium-activated potassium channels are increasingly linked to intellectual disability and loss of FMR protein causes reduced large-conductance calcium-activated potassium channel activity leading to abnormalities in synapse function. Using the cannabinoid-like large-conductance calcium-activated potassium channel activator VSN16R we rescued behavioural deficits such as repetitive behaviour, hippocampal dependent tests of daily living, hyperactivity and memory in a mouse model of fragile X syndrome. VSN16R has been shown to be safe in a phase 1 study in healthy volunteers and in a phase 2 study in patients with multiple sclerosis with high oral bioavailability and no serious adverse effects reported. VSN16R could therefore be directly utilized in a fragile X syndrome clinical study. Moreover, VSN16R showed no evidence of tolerance, which strongly suggests that chronic VSN16R may have great therapeutic value for fragile X syndrome and autism spectrum disorder. This study provides new insight into the pathophysiology of fragile X syndrome and identifies a new pathway for drug intervention for this debilitating disorder.

Novel ketone diet enhances physical and cognitive performance.

Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson's disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [31P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.-Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance.

Hippocampal lesions can enhance discrimination learning despite normal sensitivity to interference from incidental information.

Spatial properties of stimuli are sometimes encoded even when incidental to the demands of a particular learning task. Incidental encoding of spatial information may interfere with learning by (i) causing a failure to generalize learning between trials in which a cue is presented in different spatial locations and (ii) adding common spatial features to stimuli that predict different outcomes. Hippocampal lesions have been found to facilitate acquisition of certain tasks. This facilitation may occur because hippocampal lesions impair incidental encoding of spatial information that interferes with learning. To test this prediction mice with lesions of the hippocampus were trained on appetitive simple simultaneous discrimination tasks using inserts in the goal arms of a T-maze. It was found that hippocampal lesioned mice were facilitated at learning the discriminations, but they were sensitive to changes in spatial information in a manner that was similar to control mice. In a second experiment it was found that both control and hippocampal lesioned mice showed equivalent incidental encoding of egocentric spatial properties of the inserts, but both groups did not encode the allocentric information. These results demonstrate that mice show incidental encoding of egocentric spatial information that decreases the ability to solve simultaneous discrimination tasks. The normal egocentric spatial encoding in hippocampal lesioned mice contradicts theories of hippocampal function that suggest that the hippocampus is necessary for incidental learning per se, or is required for modulating stimulus representations based on the relevancy of information. The facilitated learning suggests that the hippocampal lesions can enhance learning of the same qualitative information as acquired by control mice.

Spatial maps and oscillations in the healthy hippocampus of Octodon degus, a natural model of sporadic Alzheimer's disease.

The Octodon degus is a South American rodent that is receiving increased attention as a potential model of aging and sporadic late-onset Alzheimer's disease (AD). Impairments in spatial memory tasks in Octodon degus have been reported in relation to either advanced AD-like disease or hippocampal lesion, opening the way to investigate how the function of hippocampal networks affects behavior across AD stages. However, no characterization of hippocampal electrophysiology exists in this species. Here we describe in young, healthy specimens the activity of neurons and local field potential rhythms during spatial navigation tasks with and without objects. Our findings show similarities between the Octodon degus and laboratory rodents. First, place cells with characteristics similar to those found in rats and mice exist in the CA1 subfield of the Octodon degus. Second, the introduction of objects elicits novelty-related exploration and an increase in activity of CA1 cells, with location specific and unspecific components. Third, oscillations of the local field potential are organized according to their spectral content into bands similar to those found in laboratory rodents. These results suggest a common framework of underlying mechanisms, opening the way to future studies of hippocampal dysfunction in this species associated to aging and disease.

Impaired synaptic plasticity and motor learning in mice with a point mutation implicated in human speech deficits.

The most well-described example of an inherited speech and language disorder is that observed in the multigenerational KE family, caused by a heterozygous missense mutation in the FOXP2 gene. Affected individuals are characterized by deficits in the learning and production of complex orofacial motor sequences underlying fluent speech and display impaired linguistic processing for both spoken and written language. The FOXP2 transcription factor is highly similar in many vertebrate species, with conserved expression in neural circuits related to sensorimotor integration and motor learning. In this study, we generated mice carrying an identical point mutation to that of the KE family, yielding the equivalent arginine-to-histidine substitution in the Foxp2 DNA-binding domain. Homozygous R552H mice show severe reductions in cerebellar growth and postnatal weight gain but are able to produce complex innate ultrasonic vocalizations. Heterozygous R552H mice are overtly normal in brain structure and development. Crucially, although their baseline motor abilities appear to be identical to wild-type littermates, R552H heterozygotes display significant deficits in species-typical motor-skill learning, accompanied by abnormal synaptic plasticity in striatal and cerebellar neural circuits.

Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy.

Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS' cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer's disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R's role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug's dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding.

Efficiency, defined as the amount of work produced for a given amount of oxygen consumed, is a key determinant of endurance capacity, and can be altered by metabolic substrate supply, in that fatty acid oxidation is less efficient than glucose oxidation. It is unclear, however, whether consumption of a high-fat diet would be detrimental or beneficial for endurance capacity, due to purported glycogen-sparing properties. In addition, a high-fat diet over several months leads to cognitive impairment. Here, we tested the hypothesis that short-term ingestion of a high-fat diet (55% kcal from fat) would impair exercise capacity and cognitive function in rats, compared with a control chow diet (7.5% kcal from fat) via mitochondrial uncoupling and energy deprivation. We found that rats ran 35% less far on a treadmill and showed cognitive impairment in a maze test with 9 d of high-fat feeding, with respiratory uncoupling in skeletal muscle mitochondria, associated with increased uncoupling protein (UCP3) levels. Our results suggest that high-fat feeding, even over short periods of time, alters skeletal muscle UCP3 expression, affecting energy production and physical performance. Optimization of nutrition to maximize the efficiency of mitochondrial ATP production could improve energetics in athletes and patients with metabolic abnormalities.

Chronic bryostatin-1 rescues autistic and cognitive phenotypes in the fragile X mice.

Fragile X syndrome (FXS), an X-chromosome linked intellectual disability, is the leading monogenetic cause of autism spectrum disorder (ASD), a neurodevelopmental condition that currently has no specific drug treatment. Building upon the demonstrated therapeutic effects on spatial memory of bryostatin-1, a relatively specific activator of protein kinase C (PKC)ε, (also of PKCα) on impaired synaptic plasticity/maturation and spatial learning and memory in FXS mice, we investigated whether bryostatin-1 might affect the autistic phenotypes and other behaviors, including open field activity, activities of daily living (nesting and marble burying), at the effective therapeutic dose for spatial memory deficits. Further evaluation included other non-spatial learning and memory tasks. Interestingly, a short period of treatment (5 weeks) only produced very limited or no therapeutic effects on the autistic and cognitive phenotypes in the Fmr1 KO2 mice, while a longer treatment (13 weeks) with the same dose of bryostatin-1 effectively rescued the autistic and non-spatial learning deficit cognitive phenotypes. It is possible that longer-term treatment would result in further improvement in these fragile X phenotypes. This effect is clearly different from other treatment strategies tested to date, in that the drug shows little acute effect, but strong long-term effects. It also shows no evidence of tolerance, which has been a problem with other drug classes (mGluR5 antagonists, GABA-A and -B agonists). The results strongly suggest that, at appropriate dosing and therapeutic period, chronic bryostatin-1 may have great therapeutic value for both ASD and FXS.

Gaboxadol Normalizes Behavioral Abnormalities in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism. FXS is also accompanied by attention problems, hyperactivity, anxiety, aggression, poor sleep, repetitive behaviors, and self-injury. Recent work supports the role of γ-aminobutyric-acid (GABA), the primary inhibitory neurotransmitter in the brain, in mediating symptoms of FXS. Deficits in GABA machinery have been observed in a mouse model of FXS, including a loss of tonic inhibition in the amygdala, which is mediated by extrasynaptic GABAA receptors. Humans with FXS also show reduced GABAA receptor availability. Here, we sought to evaluate the potential of gaboxadol (also called OV101 and THIP), a selective and potent agonist for delta-subunit-containing extrasynaptic GABAA receptors (dSEGA), as a therapeutic agent for FXS by assessing its ability to normalize aberrant behaviors in a relatively uncharacterized mouse model of FXS (Fmr1 KO2 mice). Four behavioral domains (hyperactivity, anxiety, aggression, and repetitive behaviors) were probed using a battery of behavioral assays. The results showed that Fmr1 KO2 mice were hyperactive, had abnormal anxiety-like behavior, were more irritable and aggressive, and had an increased frequency of repetitive behaviors compared to wild-type (WT) littermates, which are all behavioral deficits reminiscent of individuals with FXS. Treatment with gaboxadol normalized all of the aberrant behaviors observed in Fmr1 KO2 mice back to WT levels, providing evidence of its potential benefit for treating FXS. We show that the potentiation of extrasynaptic GABA receptors alone, by gaboxadol, is sufficient to normalize numerous behavioral deficits in the FXS model using endpoints that are directly translatable to the clinical presentation of FXS. Taken together, these data support the future evaluation of gaboxadol in individuals with FXS, particularly with regard to symptoms of hyperactivity, anxiety, irritability, aggression, and repetitive behaviors.

Cortical tau burden and behavioural dysfunctions in mice exposed to monosodium glutamate in early life.

Although monosodium glutamate (MSG)-induced neurotoxicity has been recognized for decades, the potential similarities of the MSG model to Alzheimer's disease (AD)-type neuropathology have only recently been investigated. MSG-treated mice were examined behaviourally and histologically in relation to some features of AD. Four-week old mice received 5 subcutaneous MSG (2 g/kg) injections on alternate days, or saline. At age 10-12 weeks, they were given a battery of behavioural tests for species-typical behaviours and working memory. The mice were killed at 12 weeks and the brains excised. Accumulation of hyperphosphorylated tau protein was assessed in cortical and hippocampal neurons by immunohistochemistry, and in cerebral cortical homogenates. A 78% increase in cortical concentrations of phosphorylated tau protein was observed in the MSG mice. Intracellular hyperphosphorylated tau immunostaining was observed diffusely in the cortex and hippocampus, together with cortical atrophic neurons, extensive vacuolation and dysmorphic neuropil suggestive of spongiform neurodegeneration. Nest-building was significantly impaired, and spontaneous T-maze alternation was reduced, suggesting defective short-term working memory. Subcutaneous MSG treatment also induced a 56% reduction in exploratory head dips in a holeboard (P = 0.009), and a non-significant tendency for decreased burrowing behaviour (P = 0.085). These effects occurred in the absence of MSG-induced obesity or gross locomotor deficits. The findings point to subcutaneous MSG administration in early life as a cause of tau pathology and compromised species-typical behaviour in rodents. Determining whether MSG can be useful in modelling AD requires further studies of longer duration and full behavioural characterization.

Marked for life? Effects of early cage-cleaning frequency, delivery batch, and identification tail-marking on rat anxiety profiles.

Daily handling of preweanling rats reduces their adult anxiety. Even routine cage-cleaning, involving handling, reduces adult anxiety compared with controls. Cage-cleaning regimes differ between animal breeders, potentially affecting rodent anxiety and experimental results. Here, 92 adult male rats given different cage-cleaning rates as pups, were compared on plus-maze, hyponeophagia, corticosterone, and handling tests. They were pair-housed and half were tail-marked for identification. Anxiety/stress profiles were unaffected by cage-cleaning frequency, suggesting that commercial-typical differences in husbandry contribute little variance to adult rat behavior. However, delivery batch affected some elevated plus-maze measures. Also, tail-marked rats spent three times longer on the plus-maze open arms than their unmarked cagemates, suggesting reduced anxiety, yet paradoxically they showed greater chromodacryorrhoea responses to handling, implying increased aversion to human contact. A follow-up study showed that rats avoided the odor released from the marker pen used. Thus, apparently trivial aspects of procedure can greatly affect experimental results.

The long-lived Octodon degus as a rodent drug discovery model for Alzheimer's and other age-related diseases.

Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disease. Despite decades of research, no disease modifying therapy is available and a change of research objectives and/or development of novel research tools may be required. Much AD research has been based on experimental models using animals with a short lifespan that have been extensively genetically manipulated and do not represent the full spectrum of late-onset AD, which make up the majority of cases. The aetiology of AD is heterogeneous and involves multiple factors associated with the late-onset of the disease like disturbances in brain insulin, oxidative stress, neuroinflammation, metabolic syndrome, retinal degeneration and sleep disturbances which are all progressive abnormalities that could account for many molecular, biochemical and histopathological lesions found in brain from patients dying from AD. This review is based on the long-lived rodent Octodon degus (degu) which is a small diurnal rodent native to South America that can spontaneously develop cognitive decline with concomitant phospho-tau, ß-amyloid pathology and neuroinflammation in brain. In addition, the degu can also develop several other conditions like type 2 diabetes, macular and retinal degeneration and atherosclerosis, conditions that are often associated with aging and are often comorbid with AD. Long-lived animals like the degu may provide a more realistic model to study late onset AD.

Increased expression of the 5-HT transporter confers a low-anxiety phenotype linked to decreased 5-HT transmission.

A commonly occurring polymorphic variant of the human 5-hydroxytryptamine (5-HT) transporter (5-HTT) gene that increases 5-HTT expression has been associated with reduced anxiety levels in human volunteer and patient populations. However, it is not known whether this linkage between genotype and anxiety relates to variation in 5-HTT expression and consequent changes in 5-HT transmission. Here we test this hypothesis by measuring the neurochemical and behavioral characteristics of a mouse genetically engineered to overexpress the 5-HTT. Transgenic mice overexpressing the human 5-HTT (h5-HTT) were produced from a 500 kb yeast artificial chromosome construct. These transgenic mice showed the presence of h5-HTT mRNA in the midbrain raphe nuclei, as well as a twofold to threefold increase in 5-HTT binding sites in the raphe nuclei and a range of forebrain regions. The transgenic mice had reduced regional brain whole-tissue levels of 5-HT and, in microdialysis experiments, decreased brain extracellular 5-HT, which reversed on administration of the 5-HTT inhibitor paroxetine. Compared with wild-type mice, the transgenic mice exhibited a low-anxiety phenotype in plus maze and hyponeophagia tests. Furthermore, in the plus maze test, the low-anxiety phenotype of the transgenic mice was reversed by acute administration of paroxetine, suggesting a direct link between the behavior, 5-HTT overexpression, and low extracellular 5-HT. In toto, these findings demonstrate that associations between increased 5-HTT expression and anxiety can be modeled in mice and may be specifically mediated by decreases in 5-HT transmission.

A within-subjects, within-task demonstration of intact spatial reference memory and impaired spatial working memory in glutamate receptor-A-deficient mice.

Gene-targeted mice lacking the AMPA receptor subunit glutamate receptor-A (GluRA) (GluR1) and wild-type controls were compared on a radial-maze task in which the same three of six arms were always baited, but in which the rewards of milk were not replaced within a trial. This procedure allowed not only a within-subjects but also a within-trials assessment of both spatial working memory (WM) and reference memory (RM) in GluRA-/- mice, using identical spatial cues. In experiment 1, the GluRA-/- mice made more WM and RM errors during task acquisition. However, separate groups of GluRA-/- and wild-type mice (experiment 2) acquired a purely RM version of the task at a similar rate, using a paradigm with which it was not possible to make WM errors (doors prevented mice from re-entering an arm that they had already visited on that trial). In contrast, mice with hippocampal lesions were dramatically impaired. These results are consistent with the possibility that the WM impairment in the GluRA-/- mice during experiment 1 produced interference that disrupted RM acquisition. A WM component was therefore introduced after RM acquisition in experiment 2 (i.e., the mice were no longer prevented from re-entering a previously visited arm). The GluRA-/- mice now made considerably more WM errors than did wild-type mice, but simultaneously, RM was only mildly and transiently impaired. These experiments provide additional evidence of a selective spatial WM deficit coexisting with intact spatial RM acquisition in GluRA-/- mice, suggesting that different neuronal mechanisms within the hippocampus may support these different kinds of information processing.

The role of hippocampal glutamate receptor-A-dependent synaptic plasticity in conditional learning: the importance of spatiotemporal discontiguity.

Gene-targeted mice lacking the AMPA receptor subunit glutamate receptor-A (GluR-A or GluR1) and mice with cytotoxic hippocampal lesions were compared with wild-type and sham-operated controls, respectively, on a conditional learning task using an elevated T-maze. Floor inserts (white perspex vs wire mesh) provided a conditional cue indicating in which goal arm a food reward was to be found. The relationship between the floor insert and the rewarded goal arm was constant throughout the experiment. Both lesioned and knock-out mice were able to acquire the task if the floor inserts extended throughout the entire maze, including the start arm and both goal arms. In contrast, both lesioned and knock-out mice were unable to acquire the task if the floor inserts were only present in the start arm of the maze. The absence of the conditional cue (the floor insert) at the time when the place-reward association was experienced thus critically determined whether or not the mice were impaired. We suggest that hippocampal GluR-A-dependent synaptic plasticity contributes to a memory system in rodents for encoding both the spatial and temporal contexts (the where and the when) associated with a particular event.

Hippocampal lesions, species-typical behaviours and anxiety in mice.

The hippocampus is believed to play an important role in spatial cognition and anxiety. Much of the supporting evidence is derived from rat studies. Recent reports on hippocampal lesioned mice also showed impairments in spatial function, but anxiety was not uniformly diminished. There were, however, striking impairments in several "species typical" behaviours; lesioned mice made poorer nests, and hoarded and burrowed less. In the present experiments, mice with excitotoxic hippocampal lesions were tested in a well-established anxiety paradigm, the light-dark box. As in previous anxiety tests, the results were mixed; some measures (reduced dark time) suggested lesioned mice were less anxious; others (fewer light-dark transits) suggested greater anxiety. However, lesioned mice only made fewer transits when the door was small. This suggested that the tendency to enter small holes, so characteristic of small rodents, was reduced; subsequent tests showed lesioned mice preferred to explore in an alley rather than enter its attached tunnels. Further tests of "species typical" behaviours revealed that lesioned mice spent less time digging and climbing, and made less use of cardboard shelters in their cages. This was not due to inactivity; lesions did not reduce grooming or locomotion. Finally, tests of hyponeophagia showed hippocampal lesions reduced this measure of anxiety, so long as the control baseline was sufficiently high. Overall, the results suggest that the hippocampus is important in many species-typical behaviours, potentially influencing performance in a range of behavioural tests. However, species-typical behaviours offer easy and economical ways to test for hippocampal dysfunction, for example, in genetically modified mice.

Hippocampal scrapie infection impairs operant DRL performance in mice.

In differential reinforcement of low rates of responding (DRL) tasks, animals are trained to respond for rewards that become available only after some set time has elapsed since the animal's previous response. DRL performance is impaired by hippocampal lesions regardless of their precise location, and can be measured using automated operant equipment, whereas spatial tasks are selectively impaired by dorsal, but not ventral hippocampal lesions, and are typically conducted by hand. Earlier studies of prion infection following dorsal hippocampal micro-injections of scrapie have shown clear impairments of spatial alternation, but these occurred significantly later than dysfunction in hippocampus-dependent 'domestic' tasks such as nesting or burrowing. In the present experiment, mice were trained to respond on an automated DRL schedule prior to dorsal hippocampal ME7 scrapie injection. Post-operative DRL performance was monitored, along with performance on 'domestic' and other tests, which provided additional measures of disease progression. Animals with scrapie developed a clear DRL deficit at approximately the same time as their deficits on the other tests became apparent, and long before clinical signs were detectable. DRL deficits thus appeared earlier in the sequence of disease progression than previously reported for spatial alternation, suggesting that early signs of scrapie infection are caused in part by neuronal dysfunction extending beyond the dorsal hippocampal region of initial infection.

NNZ-2566, a novel analog of (1-3) IGF-1, as a potential therapeutic agent for fragile X syndrome.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, and many agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. In the present work, a novel pharmacological approach for FXS is investigated. NNZ-2566, a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1), was administered to fmr1 knockout mice correcting learning and memory deficits, abnormal hyperactivity and social interaction, normalizing aberrant dendritic spine density, overactive ERK and Akt signaling, and macroorchidism. Altogether, our results indicate a unique disease-modifying potential for NNZ-2566 in FXS. Most importantly, the present data implicate the IGF-1 molecular pathway in the pathogenesis of FXS. A clinical trial is under way to ascertain whether these findings translate into clinical effects in FXS patients.

Natural AD-Like Neuropathology in Octodon degus: Impaired Burrowing and Neuroinflammation.

Alzheimer's disease (AD) is the most common cause of dementia, affecting more than 36 million people worldwide. Octodon degus, a South American rodent, has been found to spontaneously develop neuropathological signs of AD, including amyloid-ß (Aß) and tau deposits, as well as a decline in cognition with age. Firstly, the present work introduces a novel behavioral assessment for O. degus - the burrowing test - which appears to be a useful tool for detecting neurodegeneration in the O. degus model for AD. Such characterization has potentially wide-ranging implications, because many of these changes in species-typical behaviors are reminiscent of the impairments in activities of daily living (ADL), so characteristic of human AD. Furthermore, the present work characterizes the AD-like neuropathology in O. degus from a gene expression point of view, revealing a number of previously unreported AD biomarkers, which are found in human AD: amyloid precursor protein (APP), apolipoprotein E (ApoE), oxidative stress-related genes from the NFE2L2 and PPAR pathway, as well as pro-inflammatory cytokines and complement proteins, in agreement with the known link between neurodegeneration and neuroinflammation. In summary, the present results confirm a natural neuropathology in O. degus with similar characteristics to AD at behavioral, cellular and molecular levels. These characteristics put O. degus in a singular position as a natural rodent model for research into AD pathogenesis and therapeutics against AD.