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Progress in earlier detection and clinical management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available as a result of technical challenges. We developed a transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein-coding genes. RNA-seq of neonatal forebrains demonstrates that TcHSA21rat expresses HSA21 genes and has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a "Down syndrome karyotype" in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, which is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development., Competing Interests: Declaration of interests M.O. is a CEO, employee, and shareholder of Trans Chromosomics, Inc., and S.A., H.T., and S.T. are employees of Trans Chromosomics, Inc. Other authors declare no conflicts of interest., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Cocaine blocks dopamine uptake via dopamine transporter (DAT) on plasma membrane of neuron cells and, as a result, produces the high and induces DAT trafficking to plasma membrane which contributes to the drug seeking or craving. In this study, we first examined the dose dependence of cocaine-induced DAT trafficking and hyperactivity in rats, demonstrating that cocaine at an intraperitoneal dose of 10 mg/kg or higher led to redistribution of most DAT to the plasma membrane while inducing significant hyperactivity in rats. However, administration of 5-mg/kg cocaine (ip) did not significantly induce DAT trafficking or hyperactivity in rats. So the threshold (intraperitoneal) dose of cocaine that can significantly induce DAT trafficking or hyperactivity should be between 5 and 10 mg/kg. These data suggest that when a cocaine dose is high enough to induce significant hyperactivity, it can also significantly induce DAT trafficking to the plasma membrane. Further, the threshold brain cocaine concentration required to induce significant hyperactivity and DAT trafficking was estimated to be ~2.0 ± 0.8 μg/g. Particularly, for treatment of cocaine abuse, previous studies demonstrated that an exogenous cocaine-metabolizing enzyme, for example, CocH3-Fc(M3), can effectively block cocaine-induced hyperactivity. However, it was unknown whether an enzyme could also effectively block cocaine-induced DAT trafficking to the plasma membrane. This study demonstrates, for the first time, that the enzyme is also capable of effectively blocking cocaine from reaching the brain even with a lethal dose of 60-mg/kg cocaine (ip) and, thus, powerfully preventing cocaine-induced physiological effects such as the hyperactivity and DAT trafficking., (© 2021 Society for the Study of Addiction.)

There is evidence that glycemic fluctuations trigger vascular-mediated dysfunction in both the retina and the striatopallidal regions in patients with diabetes. The latter is associated with a variety of hyperkinetic disorders that are rare but disabling and potentially preventable. We conducted a systematic review of the potential association between diabetic retinopathy and the risk and prognosis of hyperkinetic disorders in patients with diabetes. We identified a total of 461 articles and 147 were eligible for review. Nine out of 147 articles (6.12%) reported 13 patients with information on diabetic retinopathy. Glycemic fluctuations were present at onset in 10 patients (77%) and retinopathy was present in nine of them (69.23%). The degree of retinopathy was reported in four patients. Two had severe, bilateral proliferative retinopathy, one had moderate-to-severe non-proliferative retinopathy and one had non-proliferative retinopathy. In the nine patients with retinopathy, hyperkinesia persisted, required higher doses of dopamine receptor antagonists or deep brain stimulation. Retinopathy was absent in four cases (30.77%). In these patients, hyperkinesia resolved spontaneously or with lower doses of dopamine receptor antagonists. Diabetic retinopathy could be an indirect marker of striatopallidal microangiopathy in patients with diabetes. The severity of retinopathy may be associated with increased risk or worse prognosis for patients who develop hyperkinetic disorders of the diabetic striatopathy spectrum. Early detection of retinopathy could identify patients in which avoiding glycemic fluctuations may prevent the development of striatopathy and hyperkinetic disorders., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: This is the first case-control study investigating an association between gallbladder hyperkinesia and symptomatic acalculous chronic cholecystitis., Methods: This retrospective study in a single academic center compared resolution of biliary pain in adults with gallbladder hyperkinesia, defined as a hepatobiliary iminodiacetic acid scan ejection fraction ≥80%, undergoing cholecystectomy (study group) with those treated medically without cholecystectomy (control group). Of 1,477 hepatobiliary iminodiacetic acid scans done between 2013 and 2018, a total of 296 adults without gallstones had an ejection fraction ≥80%, of whom 46 patients met predetermined eligibility criteria. Demographic data, hepatobiliary iminodiacetic acid scan ejection fraction, chronicity of pain, and resolution of pain were compared between groups., Results: Demographics (mean ± standard deviation) in the control group (n = 25) and in the study group (n = 21) were, respectively, age 40 y ± 16 y and 39 y ± 14 y, body mass index 28.9 ± 5.2 and 29.1 ± 7.1 kg/m 2 , with 15 (60%) and 18 (86%) females in each. Resolution of pain after cholecystectomy occurred in 18 of 21 patients (86%); however, pain persisted in 20 of 25 patients (80%) treated medically after mean follow-up of 36 ± 28 months (range 10-120 months) (P < .01). Pain resolution with cholecystectomy was independent of demographic variables, hepatobiliary iminodiacetic acid scan ejection fraction, and chronicity of pain. The odds of pain resolution was 19.7 times greater with cholecystectomy than without (odds ratio, 19.7; 95% confidence interval, 4.34, 89.43; P < .01), and remained robust even with the odds adjusted for each covariate. Gallbladder histopathology confirmed chronic cholecystitis in all 21 cholecystectomy specimens., Conclusion: Symptomatic gallbladder hyperkinesia could be a new indication for cholecystectomy in adults., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cyclin-dependent kinase-like 5 (CDKL5), a serine-threonine kinase encoded by an X-linked gene, is highly expressed in the mammalian forebrain. Mutations in this gene cause CDKL5 deficiency disorder, a neurodevelopmental encephalopathy characterized by early-onset seizures, motor dysfunction, and intellectual disability. We previously found that mice lacking CDKL5 exhibit hyperlocomotion and increased impulsivity, resembling the core symptoms in attention-deficit hyperactivity disorder (ADHD). Here, we report the potential neural mechanisms and treatment for hyperlocomotion induced by CDKL5 deficiency. Our results showed that loss of CDKL5 decreases the proportion of phosphorylated dopamine transporter (DAT) in the rostral striatum, leading to increased levels of extracellular dopamine and hyperlocomotion. Administration of methylphenidate (MPH), a DAT inhibitor clinically effective to improve symptoms in ADHD, significantly alleviated the hyperlocomotion phenotype in Cdkl5 null mice. In addition, the improved behavioral effects of MPH were accompanied by a region-specific restoration of phosphorylated dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa, a key signaling protein for striatal motor output. Finally, mice carrying a Cdkl5 deletion selectively in DAT-expressing dopaminergic neurons, but not dopamine receptive neurons, recapitulated the hyperlocomotion phenotype found in Cdkl5 null mice. Our findings suggest that CDKL5 is essential to control locomotor behavior by regulating region-specific dopamine content and phosphorylation of dopamine signaling proteins in the striatum. The direct, as well as indirect, target proteins regulated by CDKL5 may play a key role in movement control and the therapeutic development for hyperactivity disorders., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Developmental ethanol exposure is a well-known cause of lifelong cognitive deficits, behavioral hyperactivity, emotional dysregulation, and more. In healthy adults, sleep is thought to have a critical involvement in each of these processes. Our previous work has demonstrated that some aspects of cognitive impairment in adult mice exposed at postnatal day 7 (P7) to ethanol (EtOH) correlate with slow-wave sleep (SWS) fragmentation (Wilson et al., 2016). We and others have also previously demonstrated that co-treatment with LiCl on the day of EtOH exposure prevents many of the anatomical and physiological impairments observed in adults. Here we explored cognitive function, diurnal rhythms (activity, temperature), SWS, and parvalbumin (PV) and perineuronal net (PNN)-positive cell densities in adult mice that had received a single day of EtOH exposure on P7 and saline-treated littermate controls. Half of the animals also received a LiCl injection on P7. The results suggest that developmental EtOH resulted in adult behavioral hyperactivity, cognitive impairment, and reduced SWS compared to saline controls. Both of these effects were reduced by LiCl treatment on the day of EtOH exposure. Finally, developmental EtOH resulted in decreased PV/PNN-expressing cells in retrosplenial (RS) cortex and dorsal CA3 hippocampus at P90. As with sleep and behavioral activity, LiCl treatment reduced this decrease in PV expression. Together, these results further clarify the long-lasting effects of developmental EtOH on adult behavior, physiology, and anatomy. Furthermore, they demonstrate the neuroprotective effects of LiCl co-treatment on this wide range of developmental EtOH's long-lasting consequences., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

The zinc-finger SWIM domain-containing protein 6 (ZSWIM6) is a protein of unknown function that has been associated with schizophrenia and limited educational attainment by three independent genome-wide association studies. Additionally, a putatively causal point mutation in ZSWIM6 has been identified in several cases of acromelic frontonasal dysostosis with severe intellectual disability. Despite the growing number of studies implicating ZSWIM6 as an important regulator of brain development, its role in this process has never been examined. Here, we report the generation of Zswim6 knockout mice and provide a detailed anatomical and behavioral characterization of the resulting phenotype. We show that Zswim6 is initially expressed widely during embryonic brain development but becomes restricted to the striatum postnatally. Loss of Zswim6 causes a reduction in striatal volume and changes in medium spiny neuron morphology. These changes are associated with alterations in motor control, including hyperactivity, impaired rotarod performance, repetitive movements, and behavioral hyperresponsiveness to amphetamine. Together, our results show that Zswim6 is indispensable to normal brain function and support the notion that Zswim6 might serve as an important contributor to the pathogenesis of schizophrenia and other neurodevelopmental disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The adolescent period in mammals is a critical period of brain maturation and thus represents a time of susceptibility to environmental insult, e.g. psychosocial stress and/or drugs of abuse, which may cause lasting impairments in brain function and behavior and even precipitate symptoms in at-risk individuals. One likely effect of these environmental insults is to increase oxidative stress in the developing adolescent brain. Indeed, there is increasing evidence that redox dysregulation plays an important role in the development of schizophrenia and other neuropsychiatric disorders and that GABA interneurons are particularly susceptible to alterations in oxidative stress. The current study sought to model this adolescent neurochemical "stress" by exposing mice to the dopamine transporter inhibitor GBR12909 (5mg/kg; IP) during adolescence (postnatal day 35-44) and measuring the resultant effect on locomotor behavior and probabilistic reversal learning as well as GABAergic interneurons and oxidative stress in adulthood. C57BL6/J mice exposed to GBR12909 showed increased activity in a novel environment and increased impulsivity as measured by premature responding in the probabilistic reversal learning task. Adolescent GBR12909-exposed mice also showed decreased parvalbumin (PV) immunoreactivity in the prefrontal cortex, which was accompanied by increased oxidative stress in PV+ neurons. These findings indicate that adolescent exposure to a dopamine transporter inhibitor results in loss of PV in GABAergic interneurons, elevations in markers of oxidative stress, and alterations in behavior in adulthood., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

The programming of cell fate by transcription factors requires precise regulation of their time and level of expression. The LIM-homeodomain transcription factor Islet1 (Isl1) is involved in cell-fate specification of motor neurons, and it may play a similar role in the inner ear. In order to study its role in the regulation of vestibulo-motor development, we investigated a transgenic mouse expressing Isl1 under the Pax2 promoter control (Tg +/- ). The transgenic mice show altered level, time, and place of expression of Isl1 but are viable. However, Tg +/- mice exhibit hyperactivity, including circling behavior, and progressive age-related decline in hearing, which has been reported previously. Here, we describe the molecular and morphological changes in the cerebellum and vestibular system that may cause the hyperactivity of Tg +/- mice. The transgene altered the formation of folia in the cerebellum, the distribution of calretinin labeled unipolar brush cells, and reduced the size of the cerebellum, inferior colliculus, and saccule. Age-related progressive reduction of calbindin expression was detected in Purkinje cells in the transgenic cerebella. The hyperactivity of Tg +/- mice is reduced upon the administration of picrotoxin, a non-competitive channel blocker for the γ-aminobutyric acid (GABA) receptor chloride channels. This suggests that the overexpression of Isl1 significantly affects the functions of GABAergic neurons. We demonstrate that the overexpression of Isl1 affects the development and function of the cerebello-vestibular system, resulting in hyperactivity.

Background: Cervical dystonias have a variable presentation and underlying etiology, but collectively represent the most common form of focal dystonia. There are a number of known genetic forms of dystonia (DYT1-27); however the heterogeneity of disease presentation does not always make it easy to categorize the disease by phenotype-genotype comparison., Case Presentation: In this report, we describe a 53-year-old female who presented initially with hand tremor following a total hip arthroplasty. The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm. Whole exome sequencing of the patient revealed a novel heterozygous missense variant (Chr11(GRCh38): g.26525644C > G; NM&#95;031418.2(ANO3): c.702C > G; NP&#95;113606.2. p.C234W) in exon 7 in the ANO3 gene., Conclusions: ANO3 encodes anoctamin-3, a Ca +2 -dependent phospholipid scramblase expressed in striatal-neurons, that has been implicated in autosomal dominant craniocervical dystonia (Dystonia-24, DYT24, MIM# 615034). To date, only a handful of cases of DYT-24 have been described in the literature. The complex clinical presentation of the patient described includes hyperkinesias, complex motor movements, and vocal tics, which have not been reported in other patients with DYT24. This report highlights the utility of using clinical whole exome sequencing in patients with complex neurological phenotypes that would not normally fit a classical presentation of a defined genetic disease.

Selenoprotein T (SelT) is a newly discovered thioredoxin-like protein, which is abundantly but transiently expressed in the neural lineage during brain ontogenesis. Because its physiological function in the brain remains unknown, we developed a conditional knockout mouse line (Nes-Cre/SelT fl/fl ) in which SelT gene is specifically disrupted in nerve cells. At postnatal day 7 (P7), these mice exhibited reduced volume of different brain structures, including hippocampus, cerebellum, and cerebral cortex. This phenotype, which is observed early during the first postnatal week, culminated at P7 and was associated with increased loss of immature neurons but not glial cells, through apoptotic cell death. This phenomenon was accompanied by elevated levels of intracellular reactive oxygen species, which may explain the increased neuron demise and reduced brain structure volumes. At the second postnatal week, an increase in neurogenesis was observed in the cerebellum of Nes-Cre/SelT fl/fl mice, suggesting the occurrence of developmental compensatory mechanisms in the brain. In fact, the brain volume alterations observed at P7 were attenuated in adult mice. Nevertheless, SelT mutant mice exhibited a hyperactive behavior, suggesting that despite an apparent morphological compensation, SelT deficiency leads to cerebral malfunction in adulthood. Altogether, these results demonstrate that SelT exerts a neuroprotective role which is essential during brain development, and that its loss impairs mice behavior.

Unlabelled: Serotonin (5-HT) is a crucial neuromodulator linked to many psychiatric disorders. However, after more than 60 years of study, its role in behavior remains poorly understood, in part because of a lack of methods to target 5-HT synthesis specifically in the adult brain. Here, we have developed a genetic approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system by stereotaxic injection of an adeno-associated virus expressing Cre recombinase (AAV-Cre) into the midbrain/pons of mice carrying a loxP-conditional tryptophan hydroxylase 2 (Tph2) allele. We investigated the behavioral effects of deficient brain 5-HT synthesis and discovered a unique composite phenotype. Surprisingly, adult 5-HT deficiency did not affect anxiety-like behavior, but resulted in a robust hyperactivity phenotype in novel and home cage environments. Moreover, loss of 5-HT led to an altered pattern of circadian behavior characterized by an advance in the onset and a delay in the offset of daily activity, thus revealing a requirement for adult 5-HT in the control of daily activity patterns. Notably, after normalizing for hyperactivity, we found that the normal prolonged break in nocturnal activity (siesta), a period of rapid eye movement (REM) and non-REM sleep, was absent in all animals in which 5-HT deficiency was verified. Our findings identify adult 5-HT as a requirement for siestas, implicate adult 5-HT in sleep-wake homeostasis, and highlight the importance of our adult-specific 5-HT-synthesis-targeting approach in understanding 5-HT's role in controlling behavior., Significance Statement: Serotonin (5-HT) is a crucial neuromodulator, yet its role in behavior remains poorly understood, in part because of a lack of methods to target specifically adult brain 5-HT synthesis. We developed an approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system. Using this technique, we discovered that adult 5-HT deficiency led to a novel compound phenotype consisting of hyperactivity, disrupted circadian behavior patterns, and elimination of siestas, a period of increased sleep during the active phase. These findings highlight the importance of our approach in understanding 5-HT's role in behavior, especially in controlling activity levels, circadian behavior, and sleep-wake homeostasis, behaviors that are disrupted in many psychiatric disorders such as attention deficit hyperactivity disorder., (Copyright © 2016 the authors 0270-6474/16/369828-15$15.00/0.)

Purpose: Paroxysmal sympathetic hyperactivity is a complication of brain injury that has mainly been described in the adult brain injury literature., Methods: We present a case series of three pediatric patients that developed paroxysmal sympathetic hyperactivity of varying severity following hypoxic brain injury., Results: Comparison of brain magnetic resonance imaging revealed bilateral and symmetric global ischemic changes in all three cases. However, the thalamus was not affected in the patient with the mild case of paroxysmal sympathetic hyperactivity. In contrast, bilateral and symmetric damage to the thalamus was observed in the two severe cases., Conclusions: Our case series suggests that in hypoxic brain injury, evidence of bilateral ischemic injury to the thalamus on magnetic resonance imaging may be an important early predictor of severity and length of paroxysmal sympathetic hyperactivity. While this is an interesting observation, definite proof of our hypothesis requires further research including analysis of larger numbers of patients and comparison of MRI findings in children with hypoxic brain injury that do not develop paroxysmal sympathetic hyperactivity.

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We report the case of a 4-year-old girl who presented with paroxysmal sympathetic hyperactivity (PSH), after developing severe hypoxic-ischemic-encephalopathy because of cardiopulmonary arrest. She showed dramatic paroxysmal sympathetic activity with dystonia. She was treated with wide variety of medications against PSH, which were found to be effective in previous studies. Among them, morphine, bromocriptine, propranolol, and clonidine were effective in reducing the frequency of her attacks while gabapentin, baclofen, dantrolene, and benzodiazepine were ineffective. Though the paroxysms decreased markedly after the treatment, they could not be completely controlled beyond 500 days. Following the treatment, levels of plasma catecholamines and their urinary metabolites decreased to normal during inter- paroxysms. However, once a paroxysm had recurred, these levels were again very high. This case study is considered significant for two rea- sons. One is that PSH among children have been rarely reported, and the other is that this case of prolonged PSH delineated the transition of plasma catecholamines during the treatment. The excitatory: inhibitory ratio (EIR) model proposed by Baguley was considered while dis- cussing drug sensitivity in this case. Accumulation of similar case studies will help establish more effective treatment strategies and elucidate the pathophysiology of PSH.

Traumatic brain injury (TBI) often results in structural damage and a loss of neurons that is commonly accompanied by early changes in neuronal electrical activity. Loss of neuronal activity has been hypothesized to contribute to post-traumatic epileptogenesis through the regulation of homeostatic plasticity. The existence of activity loss in cortical neurons after TBI and its subsequent transition into hyperactivity over time is not well characterized, however, particularly in models of TBI in vivo. In the current study, changes in neuronal activity in the primary motor cortex after moderate controlled cortical impact (CCI) in mice were studied using a single-unit recording technique in vivo. Recordings were made at different time points after CCI from cortical layer V pyramidal neurons that were within 1-2 mm from the anterior edge of the injured foci. Within 1-4 h after CCI, the frequency of spontaneous single-unit activity depressed significantly, with the mean firing frequency decreasing from 2.59 ± 0.18 Hz in the sham group to 1.05 ± 0.20 Hz of the injured group. The firing frequencies recovered to the normal level at 1 day and 7 days post-CCI, but became significantly higher at 3 days and 14 days post-CCI. The results suggest that TBI caused initial loss of activity in neurons of the perilesional cortical region, which was followed by compensatory recovery and enhancement of activity. These time-dependent changes in neuronal activity may contribute to the development of hyperexcitability through homeostatic activity regulation.

Head direction (HD) cells fire when an animal faces a particular direction in its environment, and they are thought to represent the neural correlate of the animal's perceived spatial orientation. Previous studies have shown that vestibular information is critical for generating the HD signal but have not delineated whether information from all three semicircular canals or just the horizontal canals, which are primarily sensitive to angular head rotation in the horizontal (yaw) plane, are critical for the signal. Here, we monitored cell activity in the anterodorsal thalamus (ADN), an area known to contain HD cells, in epstatic circler (Ecl) mice, which have a bilateral malformation of the horizontal (lateral) semicircular canals. Ecl mice and their littermates that did not express the mutation (controls) were implanted with recording electrodes in the ADN. Results confirm the important role the horizontal canals play in forming the HD signal. Although normal HD cell activity (Raleigh's r > 0.4) was recorded in control mice, no such activity was found in Ecl mice, although some cells had activity that was mildly modulated by HD (0.4 > r > 0.2). Importantly, we also observed activity in Ecl mice that was best characterized as bursty--a pattern of activity similar to an HD signal but without any preferred firing direction. These results suggest that the neural structure for the HD network remains intact in Ecl mice, but the absence of normal horizontal canals results in an inability to control the network properly and brings about an unstable HD signal. Significance statement: Cells in the anterior dorsal thalamic nucleus normally fire in relation to the animal's directional heading with respect to the environment--so-called head direction cells. To understand how these head direction cells generate their activity, we recorded single-unit activity from the anterior dorsal thalamus in transgenic mice that lack functional horizontal semicircular canals. We show that the neural network for the head direction signal remains intact in these mice, but that the absence of normal horizontal canals results in an inability to control the network properly and brings about an unstable head direction signal., (Copyright © 2016 the authors 0270-6474/16/360741-14$15.00/0.)

High levels of impulsivity have been linked to a number of psychiatric disorders, including attention-deficit/hyperactivity disorder, drug abuse and schizophrenia. Additionally, schizophrenia patients commonly show deficits in another rather preattentive form of response inhibition, called sensorimotor gating. Given that higher-order functions, such as impulse control, are protected by early and preattentive processes, disturbed gating mechanisms may hamper more complex cognitive-executive functions. In the present study, we therefore tested whether high levels of impulsivity are accompanied by impaired sensorimotor gating in rats. High (HI) and low impulsive (LI) rats were identified based on the number of premature responses in the 5-choice serial reaction time task. Here, LI rats showed higher numbers of omission errors which may suggest attentional deficits while HI rats completed significantly less trials which could indicate a decrease in motivation. However, HI and LI rats did not differ in terms of impulsive decision-making in a delay-based decision-making T-maze task, prepulse inhibition of the acoustic startle response (a measure of sensorimotor gating mechanisms) or locomotor activity levels. Overall, our data indicate that high motor impulsivity is not a suitable predictor of deficient sensorimotor gating and is further not necessarily associated with attentional deficits and/or locomotor hyperactivity in rats., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Variants of tryptophan hydroxylase-2 (Tph2), the gene encoding enzyme responsible for the synthesis of brain serotonin (5-HT), have been associated with neuropsychiatric disorders, substance abuse and addiction. This study assessed the effect of Tph2 gene deletion on motor behavior and found that motor activity induced by 2.5 and 5 mg/kg amphetamine was enhanced in Tph2(-/-) mice. Using the in vivo microdialysis technique we found that the ability of amphetamine to stimulate noradrenaline (NA) release in the striatum was reduced by about 50% in Tph2(-/-) mice while the release of dopamine (DA) was not affected. Tph2 deletion did not affect the release of NA and DA in the prefrontal cortex. The role of endogenous 5-HT in enhancing the effect of amphetamine was confirmed showing that treatment with the 5-HT precursor 5-hydroxytryptophan (10 mg/kg) restored tissue and extracellular levels of brain 5-HT and the effects of amphetamine on striatal NA release and motor activity in Tph2(-/-) mice. Treatment with the NA precursor dihydroxyphenylserine (400 mg/kg) was sufficient to restore the effect of amphetamine on striatal NA release and motor activity in Tph2(-/-) mice. These findings indicate that amphetamine-induced hyperactivity is attenuated by endogenous 5-HT through the inhibition of striatal NA release. Tph2(-/-) mice may be a useful preclinical model to assess the role of 5-HT-dependent mechanisms in the action of psychostimulants. Acute sensitivity to the motor effects of amphetamine has been associated to increased risk of psychostimulant abuse. Here, we show that deletion of Tph2, the gene responsible for brain 5-HT synthesis, enhances the motor effect of amphetamine in mice through the inhibition of striatal NA release. This suggests that Tph2(-/-) mice is a useful preclinical model to assess the role of 5-HT-dependent mechanisms in psychostimulants action. Tph2, tryptophan hydroxylase-2., (© 2015 International Society for Neurochemistry.)

Valproate (VPA) has recently been shown to influence the behavioral effects of psycho-stimulants. Although glycogen synthase kinase 3β (GSK3β) signaling in the nucleus accumbens (NAc) plays a key role in mediating dopamine (DA)-dependent behaviors, there is less direct evidence that how VPA acts on the GSK3β signaling in the functionally distinct sub-regions of the NAc, the NAc core (NAcC) and the NAc shell (NAcSh), during psycho-stimulant-induced hyperactivity. In the present study, we applied locomotion test after acute methamphetamine (MA) (2 mg/kg) injection to identify the locomotor activity of rats received repeated VPA (300 mg/kg) pretreatment. We next measured phosphor-GSK3β at serine 9 and total GSK3β levels in NAcC and NAcSh respectively to determine the relationship between the effect of VPA on MA-induced hyperlocomotor and changes in GSK3β activity. We further investigated whether microinjection of VPA (300 μg/0.5 μl/side, once daily for 7 consecutive days) into NAcC or NAcSh could affect hyperactivity induced by MA. Our data indicated that repeated VPA treatment attenuated MA-induced hyperlocomotor, and the effect was associated with decreased levels of phosphorylated GSK3β at Ser 9 in the NAcC. Moreover, repeated bilateral intra-NAcC, but not intra-NAcSh VPA treatment, significantly attenuated MA-induced hyperactivity. Our results suggested that GSK3β activity in NAcC contributes to the inhibitory effects of VPA on MA-induced hyperactivity.

Objectives: A new form of manganese poisoning is related to the intravenous use of self-prepared methcathinone hydrochloride (ephedrone). Manganese encephalopathy typically manifests as a levodopa-resistant parkinsonism., Main Points: A 32-year-old drug-addicted man with acute gait disturbances after the ephedrone injections was presented. Choreic movements, severe postural instability, and "cock-walk" gait were observed. Magnetic resonance imaging T1 images showed high signal intensity of white matter in the basal ganglia and pituitary gland, and T2 images showed decreased signal mostly of globus pallidus with decreased N-acetylaspartate and choline levels in MR spectroscopy., Conclusions: The unusual pattern of MR imaging may explain the unusual clinical symptoms with dominant hyperkinetic syndrome.

Rationale: Alterations in brainstem circuits have been proposed as a possible mechanism underlying the etiology of mood disorders. Projections from the median raphe nucleus (MnR) modulate dopaminergic activity in the forebrain and are also part of a behavioral disinhibition/inhibition system that produces phenotypes resembling behavioral variations manifested during manic and depressive phases of bipolar disorder., Objective: The aim of this study is to assess the effect of chronic lithium treatment on behavioral disinhibition induced by MnR lesions., Methods: MnR electrolytic lesions were performed in C57BL/6J mice, with sham-operated and intact animals as control groups. Following recovery, mice were chronically treated with lithium (LiCl, added in chow) followed by behavioral testing., Results: MnR lesion induced manic-like behavioral alterations including hyperactivity in the open field (OF), stereotyped circling, anxiolytic/risk taking in the elevated plus maze (EPM) and light/dark box (LDB) tests, and increased basal body temperature. Lithium was specifically effective in reducing OF hyperactivity and stereotypy but did not reverse (EPM) or had a nonspecific effect (LDB) on anxiety/risk-taking measures. Additionally, lithium decreased saccharin preference and prevented weight loss during single housing., Conclusions: Our data support electrolytic lesions of the MnR as an experimental model of a hyper-excitable/disinhibited phenotype consistent with some aspects of mania that are attenuated by the mood stabilizer lithium. Given lithium's relatively specific efficacy in treating mania, these data support the hypothesis that manic symptoms derive not only from the stimulation of excitatory systems but also from inactivation or decreased activity of inhibitory mechanisms.

The leucine-rich repeat kinase 2 mutation G2019S in the kinase-domain is the most common genetic cause of Parkinson's disease. To investigate the impact of the G2019S mutation on motor activity in vivo, a longitudinal phenotyping approach was developed in knock-in (KI) mice bearing this kinase-enhancing mutation. Two cohorts of G2019S KI mice and wild-type littermates (WT) were subjected to behavioral tests, specific for akinesia, bradykinesia and overall gait ability, at different ages (3, 6, 10, 15 and 19months). The motor performance of G2019S KI mice remained stable up to the age of 19months and did not show the typical age-related decline in immobility time and stepping activity of WT. Several lines of evidence suggest that enhanced LRRK2 kinase activity is the main contributor to the observed hyperkinetic phenotype of G2019S KI mice: i) KI mice carrying a LRRK2 kinase-dead mutation (D1994S KD) showed a similar progressive motor decline as WT; ii) two LRRK2 kinase inhibitors, H-1152 and Nov-LRRK2-11, acutely reversed the hyperkinetic phenotype of G2019S KI mice, while being ineffective in WT or D1994S KD animals. LRRK2 target engagement in vivo was further substantiated by reduction of LRRK2 phosphorylation at Ser935 in the striatum and cortex at efficacious doses of Nov-LRRK2-11, and in the striatum at efficacious doses of H-1152. In summary, expression of the G2019S mutation in the mouse LRRK2 gene confers a hyperkinetic phenotype that is resistant to age-related motor decline, likely via enhancement of LRRK2 kinase activity. This study provides an in vivo model to investigate the effects of LRRK2 inhibitors on motor function., (Copyright © 2014. Published by Elsevier Inc.)

We report a female patient who presented with intractable epileptic seizures, profound developmental delay since early infancy, and hyperkinetic movements with hand stereotypies. The patient initially developed focal seizures with multiple foci at 3 months of age. Thereafter, the seizures evolved to frequent episodes of hyperthermia-induced status epilepticus. A novel de novo SCN1A mutation was identified by whole-exome sequence analysis. This case demonstrates that SCN1A mutations may cause movement disorders as an atypical phenotype and the case history of this patient may expand our understanding of the clinical spectrum of SCN1A-associated epileptic encephalopathy. [Published with video sequences].

Activity-based anorexia (ABA) consists of a procedure that involves the simultaneous exposure of animals to a restricted feeding schedule, while free access is allowed to an activity wheel. Under these conditions, animals show a progressive increase in wheel running, a reduced efficiency in food intake to compensate for their increased activity, and a severe progression of weight loss. Due to the parallelism with the clinical manifestations of anorexia nervosa including increased activity, reduced food intake and severe weight loss, the ABA procedure has been proposed as the best analog of human anorexia nervosa (AN). Thus, ABA research could both allow a better understanding of the mechanisms underlying AN and generate useful leads for treatment development in AN., (Copyright © 2014 John Wiley & Sons, Inc.)

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs.

According to memory reconsolidation theory, when long-term memory is reactivated by relevant clues, the memory traces become labile, which can be altered by pharmacological manipulations. Accumulating evidence reveals that memory related to drug abuse can be erased by disrupting reconsolidation process. We used an animal model that could simultaneously measure conditioned hyperactivity and locomotor sensitization induced by morphine. β-Adrenoceptor antagonist propranolol or saline were administered following conditioned stimuli (CS) or a small dose of morphine reactivation. The results showed that the conditioned hyperactivity could be disrupted by propranolol treatment following CS reactivation. However, the expression of locomotor sensitization could not be disrupted by propranolol administration following CS or morphine reactivation. Furthermore, morphine injection and propranolol intervention enhanced the locomotor sensitization effect. These data suggest that blocking the reconsolidation process can disrupt the conditioned hyperactivity induced by environmental cues associated with morphine treatment, but not morphine-induced locomotor sensitization.

Planarians, the non-parasitic flatworms, display dose-dependent, distinct (C-like and corkscrew-like) hyperkinesias upon exposure to 0.001-10 mM aqueous solutions of glutamatergic agonists (L-glutamate and N-methyl-D-aspartate (NMDA)) and 0.001-5 mM concentrations of the glutamate decarboxylase (GAD) inhibitor (semicarbazide). In the planarian seizure-like activity (PSLA) experiments the three chemoconvulsants displayed the following order of potency (EC50): L-glutamate (0.6mM)>NMDA (1.4 mM)>semicarbazide (4.5mM). Planarian hyperkinesias behavior counting experiments also revealed that riluzole (0.001 to 1mM), an anti-convulsive agent, displayed no significant behavioral activity by itself, but attenuated hyperkinesias elicited by the three chemoconvulsants targeting either glutamatergic or GABAergic neurotransmission with the following order of potency (IC50): NMDA (44.7 µM)>semicarbazide (88.3 µM)>L-glutamate (160 µM). Further, (+)-MK-801, a specific NMDA antagonist, alleviated 3mM NMDA (47%) or 3mM L-glutamate (27%) induced planarian hyperkinesias. The results provide pharmacological evidence for the presence of glutamatergic receptor-like and semicarbazide sensitive functional GAD enzyme-like proteins in planaria in addition to demonstrating, for the first time, the anti-convulsive effects of riluzole in an invertebrate model. High performance liquid chromatography coupled with fluorescence detection (HPLC-F) analysis performed on planarian extracts post no drug treatment (control) or treatment with 3mM semicarbazide, combination of 3mM semicarbazide and 0.1 mM riluzole, or 0.1 mM riluzole revealed that 3 mM semicarbazide induced 35% decrease in the GABA levels and a combination of 3mM semicarbazide and 0.1 mM riluzole induced 42% decrease in glutamate levels with respect to the control group., (Published by Elsevier B.V.)

Increased physical activity is present in 30-80% of anorexia nervosa patients. To explain the paradox of low food intake and excessive exercise in humans and other animals, it has been proposed that increased physical activity along with food restriction activates brain reward circuits and is addictive. Alternatively, the fleeing-famine hypothesis postulates that refusal of known scarce energy-low food sources and hyperactivity facilitate migration towards new habitats that potentially contain new energy-rich foodstuffs. The use of rewarding compounds that differ in energy density, such as the energy-free sweetener saccharin and the energy rich sucrose makes it possible to critically test the reward-addiction and fleeing-famine hypotheses. The aims of the present work were to study if sucrose and/or saccharin could attenuate food restriction-induced hyperactivity, weight loss, increased plasma corticosterone, and activation of brain structures involved in neuroendocrine control, energy balance, physical activity, and reward signaling in rats. Its major findings are that access to sucrose, but not to saccharin, attenuated food restriction-induced running wheel activity, weight loss, rises in plasma corticosterone, and expression of the cellular activation marker c-Fos in the paraventricular and arcuate hypothalamus and in the nucleus accumbens. These findings suggest that the energy-richness and easy availability of sucrose interrupted a fleeing-famine-like hyperactivity response. Since corticosterone mediates food restriction-induced wheel running (Duclos et al., 2009), we propose that the attenuating effect of sucrose consumption on plasma corticosterone plays a role in reduced wheel running and weight loss by lowering activation of the nucleus accumbens and arcuate hypothalamus in these animals., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

This article describes an 8-month-old boy with the full clinical spectrum anti-N-methyl-d-aspartate receptor encephalitis. He was admitted to the hospital with involuntary orofacial head movements, behavioral changes, and fluctuation in consciousness. His examination showed tongue thrusting, decreased responsiveness, and hypotonia without fever. Analysis of the cerebrospinal fluid revealed increased protein levels (62 mg/dL). The next day he developed oral dyskinesia and choreoathetosis. Video-electroencephalogram polygraphy showed coreo-dystonic movements without electrographic correlation. A putative diagnosis of autoimmune encephalopathy was made, and treatment with intravenous immunoglobulin and methylprednisolone was started, with improvement in the abnormal movements. Antibodies to the N-methyl-d-aspartate receptor were identified in the cerebrospinal fluid and blood. He began receiving immunoglobulin once a month for a year. Two months after the treatment had started, the involuntary movement disappeared and his development has been normal. N-methyl-d-aspartate receptor encephalitis is a recently identified disorder. This is the youngest case reported. Prompt diagnosis and treatment are important to obtain full recovery., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Previous research has suggested that the Wistar-Kyoto Hyperactive (WKHA) rat strain may model some of the behavioral features associated with attention-deficit/hyperactivity disorder (ADHD). We have shown that, in cerebellar-dependent eyeblink conditioning, male WKHAs emit eyeblink CRs with shortened onset latencies. To further characterize the shortened CR onset latencies seen in male WKHA rats, we examined 750-ms delay conditioning with either a tone conditional stimulus (CS) or a light CS, we extended acquisition training, and we included Wistar rats as an additional, outbred control strain. Our results indicated that WKHAs learned more quickly and showed a shortened CR onset latency to a tone CS compared to both Wistar-Kyoto Hypertensive (WKHT) and Wistars. WKHAs and Wistars show a lengthening of CR onset latency over conditioning with a tone CS and an increasing confinement of CRs to the later part of the tone CS (inhibition of delay). WKHAs learned more quickly to a light CS only in comparison to WKHTs, and showed a shortened CR onset latency only in comparison to Wistars. Wistars showed an increasing confinement of CRs to the late part of the light CS over conditioning. We used unbiased stereology to estimate the number of Purkinje and granule cells in the cerebellar cortex of the three strains. Our results indicated that WKHAs have more granule cells than Wistars and WKHTs and more Purkinje cells than Wistars. Results are discussed in terms of CS processing and cerebellar cortical contributions to EBC.

Drugs of abuse have acute and persistent effects on synapse structure and addiction-related behaviors. Trans-synaptic interactions can control synapse development, and synaptic cell adhesion molecule (SynCAM) proteins (also named nectin-like molecules) are immunoglobulin adhesion proteins that span the synaptic cleft and induce excitatory synapses. Our studies now reveal that the loss of SynCAM 1 in knockout (KO) mice reduces excitatory synapse number in nucleus accumbens (NAc). SynCAM 1 additionally contributes to the structural remodeling of NAc synapses in response to the psychostimulant cocaine. Specifically, we find that cocaine administration increases the density of stubby spines on medium spiny neurons in NAc, and that maintaining this increase requires SynCAM 1. Furthermore, mushroom-type spines on these neurons are structurally more plastic when SynCAM 1 is absent, and challenging drug-withdrawn mice with cocaine shortens these spines in SynCAM 1 KO mice. These effects are correlated with changes on the behavioral level, where SynCAM 1 contributes to the psychostimulant effects of cocaine as measured after acute and repeated administration, and in drug-withdrawn mice. Together, our results provide evidence that the loss of a synapse-organizing adhesion molecule can modulate cocaine effects on spine structures in NAc and increases vulnerability to the behavioral actions of cocaine. SynCAM-dependent pathways may therefore represent novel points of therapeutic intervention after exposure to drugs of abuse.

Systemic or intracerebral (e.g., intrahippocampal or intraamygdalar) administration of kainate, a potent neurotoxic analog of glutamate, is widely used to induce status epilepticus (SE) and subsequent development of epilepsy in rats. However, in apparent contrast to systemic administration, following intracerebral injection the proportion of rats that have been observed to generate spontaneous recurrent seizures (SRS) and the frequency of the SRS are comparatively low. More recently, it has been shown that these problems can be resolved by injecting kainate into the dorsal hippocampus of awake rats, thus avoiding the insult-modifying effects of anesthesia, which had often been used for intracerebral injection of this convulsant in previous studies. For further characterization of this model, we injected kainate (0.4 μg) unilaterally into the CA3 of the posterior hippocampus in awake rats, which induced limbic SE (ranging from 4 to 20 h) in all rats without mortality. Repeated video-EEG monitoring (24h/day, 7 days/week) for periods of 1-2.5 weeks from 1 to 8 months after SE demonstrated that 91% of the rats developed epilepsy, and that seizure frequency significantly increased over the course of the disease. Epilepsy was associated with increased behavioral excitability and impaired learning and memory in a water maze, most likely as a result of hippocampal pathology, which was characterized by extensive neuronal loss in CA3 and dentate hilus and dispersion of granule cells in the ipsilateral hippocampus. A drug trial with phenobarbital showed that all epileptic rats used in this trial responded to treatment with suppression of SRS. The data substantiate that intrahippocampal kainate injection in awake rats offers an excellent model of human temporal lobe epilepsy and indicate that this model may have particular advantages for studying mechanisms of injury-induced epilepsy and comorbidities as targets for antiepileptic and antiepileptogenic therapies., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Clinical studies have found that patients with anorexia develop high activity levels. These data suggest a possible implication of activity in the aetiology of anorexia and are in line with findings obtained in animals during experimental procedures to model interactions between activity and weight loss. Activity-based anorexia (ABA) and semistarvation-induced hyperactivity (SIH) develop when laboratory rats have food access restricted to a single period in the day and are given free access to an activity wheel. This experiment sought to show the effect on weight loss of the excessive activity normally seen in Dark Agouti rats and of hyperactivity induced by 3,4-methylenedioxymethamphetamine (MDMA). To this end, 32 female rats of the Dark Agouti strain were selected and divided into four groups in accordance with a 2 × 2 factorial design, in which one factor was treatment (saline or MDMA) and the other was access or lack of access to an activity wheel. Animals with wheel running access displayed a marked increase in running combined with accelerated weight loss. Although pharmacological treatment resulted in no observable effect on weight loss, rats treated with 12.5mg/kg MDMA generally registered more wheel running than did those treated with saline. Analysis of data on the temporal distribution of wheel running revealed an alteration in circadian activity patterns as a consequence of MDMA. These results, by showing a general high level of wheel running in Dark Agouti rats, once again emphasise the close relationship between activity and weight loss in the development of SIH and related phenomena such as ABA., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: Recent evidence supports the involvement of RCAN1 in Down syndrome and Alzheimer's disease. To better assess this, we generated and analyzed transgenic mice overexpressing human RCAN1 isoform 4 in neurons., Methods: Cognitive behavioral (Morris water maze, open field, zero maze, elevated plus maze assays); cognitive-associated proteins (CREB, ERK and Tau Western immunoblotting); motor coordination (Rotarod assay); structural abnormalities (immunohistological analyses), and proinflammatory cytokines (cytometric bead assay) were measured in young (2 month) and old (18 month) transgenics and compared with wild type controls., Results: In old mice, male but not female transgenics exhibited a significant decrease in anxiety as compared with wild type controls, whereas female but not male transgenic mice exhibited significantly less motor coordination. No differences were observed in the Morris water maze (spatial learning). pERK levels were reduced in transgenic males but not females, while no differences were observed between genotypes for pCREB and pTau. In young mice, a modest learning and exploratory behavior was observed in transgenic mice using a limited number of mice, and at higher N values, pCREB and pERK (but not pTau) levels were reduced in transgenics. No macro- and micro-scopic structural abnormalities or proinflammatory cytokine level differences were observed., Discussion: These results indicate that elevated RCAN1 isoform 4 in neurons leads to a modest cognition-related impairment that is overall stronger at 2 months, suggesting a compensatory adaptation over time. These RCAN1 isoform 4 effects may contribute to at least some of the observed phenotypes in individuals with Down syndrome and Alzheimer's.

Atypical cadherin Celsr3, a regulator of planar cell polarity, is critical for the development of the axonal blueprint. We previously showed that expression of Celsr3 is necessary to establish forebrain connections such as the anterior commissure and thalamocortical and corticospinal tracts. The requirement for Celsr3 during hippocampal wiring and its action in the hippocampus remain largely unexplored. Here, we compared the connectivity and maturation of the hippocampal formation in Celsr3|Foxg1 and Celsr3|Dlx mice. Celsr3 is inactivated in the whole telencephalon, including the hippocampal primordium, in Celsr3|Foxg1 mice, and in the early basal telencephalon, including ganglionic eminences and ventral diencephalon, in Celsr3|Dlx mice. Behavioral tests showed that both mutants were hyperactive and had impaired learning and memory. Abnormal cytoarchitecture of CA1, CA3, and dentate gyrus was found in the Celsr3|Foxg1 mutant, in which afferent and efferent hippocampal pathways, as well as intrinsic connections, were dramatically disrupted. In Celsr3|Dlx mutant mice, hippocampal cytoarchitecture was mildly affected and extrinsic and intrinsic connectivity moderately disturbed. In both mutants, pyramidal neurons in CA1 harbored atrophic dendritic trees, with decreased synapse density and increased proportion of symmetric versus asymmetric synapses, and long-term potentiation was altered. In contrast, mutant hippocampal neurons extended neurites that were normal, even longer than those of control neurons, indicating that anomalies in vivo are secondary to defective connections. Postnatal neurogenesis was preserved and mutant interneurons were able to migrate to the hippocampus. Thus, like in neocortex, Celsr3 is required for hippocampal development, connectivity and function, and for pyramidal cell maturation.

Administration of phencyclidine (PCP) is acknowledged to generate a model of psychosis in animals. With the identification of genetic susceptibility factors for schizophrenia and bipolar disorder, great efforts have been made to generate genetic animal models for major mental illnesses. As these disorders are multifactorial, comparisons among drug-induced (non-genetic) and genetic models are becoming an important issue in biological psychiatry. A major barrier is that the standard mouse strain used in the generation of genetic models is C57BL/6, whereas almost all studies with PCP-induced models have utilized other strains. To fill this technical gap, we systematically compared the behavioural changes upon PCP administration in different mouse strains, including C57BL/6N, C57BL/6J, ddY, and ICR. We observed strain differences in PCP-induced hyperlocomotion and enhanced immobility in the forced swim test (ddY>>C57BL/6N and 6J>ICR). In contrast, there was no strain difference in the impairment of recognition memory in the novel object recognition memory test after withdrawal of chronic PCP administration. This study provides practical guidance for comparing genetic with PCP-induced models of psychosis in C57BL/6. Furthermore, such strain differences may provide a clue to the biological mechanisms underlying PCP-induced endophenotypes possibly relevant to major mental illnesses.

In preterm infants, the risk to develop attention-deficit/hyperactivity disorder is 3 to 4-fold higher than in term infants. Moreover, preterm infants exhibit deficits in motor coordination and balance. Based on clinical data, higher oxygen levels in preterm infants lead to worse neurological outcome, and experimental hyperoxia causes wide-ranging cerebral changes in neonatal rodents. We hypothesize that hyperoxia in the immature brain may affect motor activity in preterm infants. We subjected newborn mice from P6 to P8 to 48 h of hyperoxia (80% O(2)) and tested motor activity in running wheels starting at adolescent age P30. Subsequently, from P44 to P53, regular wheels were replaced by complex wheels with variable crossbar positions to assess motor coordination deficits. MRI with diffusion tensor imaging was performed in the corpus callosum to determine white matter diffusivity in mice after hyperoxia at ages P30 and P53 in comparison to control animals. Adolescent mice after neonatal hyperoxia revealed significantly higher values for maximum velocity and mean velocity in regular wheels than controls (P<0.05). In the complex running wheels, however, maximum velocity was decreased in animals after hyperoxia, as compared to controls (P<0.05). Decreased fractional anisotropy and increased radial diffusion coefficient were observed in the corpus callosum of P30 and P53 mice after neonatal hyperoxia compared to control mice. Hyperoxia in the immature brain causes hyperactivity, motor coordination deficits, and impaired white matter diffusivity in adolescent and young adult mice., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Rats and mice with bilateral vestibular loss exhibit dramatic locomotor hyperactivity and circling behaviours, which to date cannot be explained. Dysfunction of the striatal dopaminergic system is responsible for a number of known movement disorders and the D(2) dopamine receptor is known to be implicated. Therefore, it is possible that changes in striatal function are responsible for locomotor hyperactivity and circling following bilateral vestibular lesions. The aim of this study was to investigate the effects of the D(2) receptor antagonist, eticlopride (0.02, 0.04 and 0.06mg/kg; s.c.), on locomotor behaviour in rats at 5 months following bilateral vestibular deafferentation (BVD), using an open field maze. The levels of the D(2) receptor protein in the striatum were measured at 1 and 6 months post-BVD using western blotting. BVD rats exhibited locomotor hyperactivity and circling, which eticlopride did not eliminate. However, BVD rats did exhibit a decreased response to the inhibitory effect of eticlopride compared to sham controls at the 0.02 mg/kg dose. There were no changes in the amount of the D(2) receptor in the striatum at 1 or 6 months post-BVD; however, D(2) receptor levels were significantly higher on the right side than the left in both sham and BVD animals. These results suggest that locomotor hyperactivity and circling behaviours following BVD are not due simply to changes in D(2) receptor protein expression in the striatum and that other neurophysiological changes in the brain account for these behaviours following BVD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Endocannabinoids are involved in excitatory neurotransmission initiated by glutamate and aspartate. The aim of the present study was to investigate the effects of the cannabinoid agonists, Δ(9)-THC and WIN55,212-2, on tissue (prefrontal cortex, dorsal striatum, nucleus accumbens, hippocampus, amygdala and hypothalamus) levels of glutamate and aspartate in two rat phenotypes, high responders (HR) and low responders (LR), differentiated according to their response to a novel environment. HR displayed increased motor activity but no difference in basal levels of glutamate and aspartate as compared to LR. Both cannabinoids increased ambulatory activity at the low doses, this effect was observed only in HR following Δ(9)-THC, but in both HR and LR following WIN55,212-2. The cannabinoids primarily increased glutamate levels in the prefrontal cortex, dorsal striatum, nucleus accumbens and hippocampus, while the high dose of WIN55,212-2 decreased glutamate levels in the amygdala and both doses in the hypothalamus; these effects appeared overall more pronounced in HR. In contrast, the cannabinoids primarily decreased aspartate levels in all brain regions, except in the dorsal striatum, where an increase was seen after both doses of Δ(9)-THC and WIN55,212-2 as well as in the nucleus accumbens after the low dose of Δ(9)-THC in HR; these effects also appeared overall more pronounced in HR. Present results show that exogenous cannabinoids affect tissue levels of glutamate and aspartate in a phenotype-, compound-, dose-, and brain region-dependent manner., (Copyright © 2011 Elsevier B.V. All rights reserved.)

LGMD2B is a frequent proximo-distal myopathy with rapid evolution after age 20. Exacerbating factors may be physical exercise and inflammation. There is very little information about the effect of sportive activity in LGMD2B, since eccentric exercise frequently results in muscle damage. LGMD2B has often an onset with myalgia and MRI imaging (STIR-sequences) shows myoedema. In a prolonged observational study of a series of 18 MM/LGMD2B patients we have studied the pattern of clinical and radiological evolution. The disease has an abrupt onset in the second decade and most patients perform sports before definite disease onset. On the basis of Gardner-Medwin and Walton scale, grade 4 is reached two years faster in patients who performed sports (over 1000 hours). Other considerations regarding pathogenetic mechanism and response to treatment show a poor response to immunosuppressive treatment of muscle inflammation. Preventing a strenuous physical activity should be recommended in patients with high CK and diagnosed or suspected to have dysferlin deficiency.

Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via β(2)-adrenoceptor (β2-AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, α(2A)-AR and α(2C)-AR (α(2A) /α(2C)-ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In α(2A) /α(2C)-ARKO versus wild-type (WT) mice, micro-computed tomographic (µCT) analysis showed increased, better connected, and more plate-shaped trabeculae in the femur and vertebra and increased cortical thickness in the vertebra, whereas biomechanical analysis showed increased tibial and femoral strength. Tibial mRNA expression of tartrate-resistant acid phosphatase (TRACP) and receptor activator of NF-κB (RANK), which are osteoclast-related factors, was lower in knockout (KO) mice. Plasma leptin and brain mRNA levels of cocaine amphetamine-regulated transcript (CART), which are factors that centrally affect bone turnover, and serum levels of estradiol were similar between mice strains. Tibial β(2)-AR mRNA expression also was similar in KO and WT littermates, whereas α(2A)-, α(2B)- and α(2C)-AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected α(2A)-, α(2B)-, α(2C)- and β(2)-ARs in osteoblasts, osteoclasts, and chondrocytes of 18.5-day-old mouse fetuses and 35-day-old mice. Finally, we showed that isolated osteoclasts in culture are responsive to the selective α(2)-AR agonist clonidine and to the nonspecific α-AR antagonist phentolamine. These findings suggest that β(2)-AR is not the single adrenoceptor involved in bone turnover regulation and show that α(2)-AR signaling also may mediate the SNS actions in the skeleton., (Copyright © 2011 American Society for Bone and Mineral Research.)

Although prion diseases are most commonly modeled using the laboratory mouse, the diversity of prion strains, behavioral testing and neuropathological assessments hamper our collective understanding of mouse models of prion disease. Here we compared several commonly used murine strains of prions in C57BL/6J female mice in a detailed home cage behavior detection system and a systematic study of pathological markers and neurotransmitter systems. We observed that mice inoculated with RML or 139A prions develop a severe hyperactivity phenotype in the home cage. A detailed assessment of pathology markers, such as microglial marker IBA1, astroglial marker GFAP and degeneration staining indicate early striatal pathology in mice inoculated with RML or 139A but not in those inoculated with 22L prions. An assessment of neuromodulatory systems including serotonin, dopamine, noradrenalin and acetylcholine showed surprisingly little decline in neuronal cell bodies or their innervations of regions controlling locomotor behavior, except for a small decrease in dopaminergic innervations of the dorsal striatum. These results implicate the dorsal striatum in mediating the major behavioral phenotype of 139A and RML prions. Further, they suggest that measurements of activity may be a sensitive manner in which to diagnose murine prion disease. With respect to neuropathology, our results indicate that pathological stains as opposed to neurotransmitter markers are much more informative and sensitive as markers of prion disease in mouse models.

Dopaminergic activity in the Nucleus Accumbens has been strongly implicated in the motor hyperactivity associated with Attention deficit hyperactivity disorder. Dopaminergic and glutamatergic terminals converge on the dendritic spines of medium spiny neurons of the nucleus accumbens core, which modulate the excitatory glutamatergic activity. In this work, a Golgi study was carried out to investigate the effects of dopamine depletion on the cytoarchitecture of dendritic spines of nucleus accumbens core medium spiny neurons. The dopaminergic system of newborn male rats was lesioned intracisternally by using 6-hydroxydopamine, and subsequently, the motor activity, spine density, and the proportion of thin, stubby, mushroom, wide, branched, and double spines was compared to those in control and intact animals. Motor activity was significantly increased in the dopamine-depleted animals and while the spine density was reduced, there was no change in the proportion of the specific types of spines. Larger thin spines were observed in the dopamine-depleted animals. Indeed, dopamine depletion may lead to spine retraction due to the disregulation of spine development, and/or an increase in glutamatergic activity. The enlargement of thin spines may suggest a compensatory mechanism to increase the efficiency of synaptic inputs in response to a decrease in spines number. Together, the present findings suggest an alteration to the excitatory/inhibitory balance on dendritic spines of medium spiny neurons of the nucleus accumbens core in hyperactive juvenile rats following early dopamine depletion., (Copyright 2010 ISDN. Published by Elsevier Ltd. All rights reserved.)

GluR2 is a subunit of the AMPA receptor, and the adenosine for the Q/R site of its pre-mRNA is converted to inosine (A-to-I conversion) by the enzyme called adenosine deaminase acting on RNA 2 (ADAR2). Failure of A-to-I conversion at this site affects multiple AMPA receptor properties, including the Ca(2+) permeability of the receptor-coupled ion channel, thereby inducing fatal epilepsy in mice (Brusa et al., 1995; Feldmeyer et al., 1999). In addition, inefficient GluR2 Q/R site editing is a disease-specific molecular dysfunction found in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients (Kawahara et al., 2004). Here, we generated genetically modified mice (designated as AR2) in which the ADAR2 gene was conditionally targeted in motor neurons using the Cre/loxP system. These AR2 mice showed a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons in the spinal cord and cranial motor nerve nuclei. Notably, neurons in nuclei of oculomotor nerves, which often escape degeneration in ALS, were not decreased in number despite a significant decrease in GluR2 Q/R site editing. All cellular and phenotypic changes in AR2 mice were prevented when the mice carried endogenous GluR2 alleles engineered to express edited GluR2 without ADAR2 activity (Higuchi et al., 2000). Thus, loss of ADAR2 activity causes AMPA receptor-mediated death of motor neurons.

Traumatic brain injury (TBI) causes a wide spectrum of consequences, such as microglial activation, cerebral inflammation, and focal and diffuse brain injury, as well as functional impairment. In this study we aimed to investigate the effects of acute treatment with minocycline as an inhibitor of microglial activation on cerebral focal and diffuse lesions, and on the spontaneous locomotor activity following TBI. The weight-drop model was used to induce TBI in mice. Microglial activation and diffuse axonal injury (DAI) were detected by immunohistochemistry using CD11b and ss-amyloid precursor protein (ss-APP) immunolabeling, respectively. Focal injury was determined by the measurement of the brain lesion volume. Horizontal and vertical locomotor activities were measured for up to 12 weeks post-injury by an automated actimeter. Minocycline or vehicle were administered three times post-insult, at 5 min (90 mg/kg i.p.), 3 h, and 9 h post-TBI (45 mg/kg i.p.). Minocycline treatment attenuated microglial activation by 59% and reduced brain lesion volume by 58%, yet it did not affect DAI at 24 h post-TBI. More interestingly, minocycline significantly decreased TBI-induced locomotor hyperactivity at 48 h post-TBI, and its effect lasted for up to 8 weeks. Taken together, the results indicate that microglial activation appears to play an important role in the development of TBI-induced focal injury and the subsequent locomotor hyperactivity, and its short-term inhibition provides long-lasting functional recovery after TBI. These findings emphasize the fact that minocycline could be a promising new therapeutic strategy for head-injured patients.

Introduction: Chorea-acanthocytosis (ChAc) is one of the neuroacanthocytosis syndromes which form a group of disorders characterized by the association of neurological abnormalities and spiculated red blood cells called acanthocytes. ChAc patients exhibit involuntary movements, psychiatric abnormalities and progressive cognitive deterioration. We report a case of ChAc in which blood smears failed to demonstrate acanthocytes., Case Report: A 26-year-old man presented since two years with hyperkinetic movements. The family history was non contributive, parents were consanguineous. Neurological examination revealed choreatic hyperkinesia and dystonia, predominant in the orofacial region. Mild cognitive decline and behavior abnormalities were noted with repetitive activities. Brain MRI showed striatal atrophy. Molecular testing for Huntington's disease was negative. Routine biological screening was normal except for elevated CPK and LDH. Copper and ceruloplasmin blood levels were normal, as well as purine metabolism and lipoproteins. Further screening for metabolic diseases showed no significant abnormality. Expression of Kell antigens was normal. In several blood smears no acanthocytes were seen. Electromyographic studies showed slight neuropathic changes. Despite the absence of acanthocytes, chorein western blot was performed on blood samples which revealed an absent or markedly reduced level of chorein in erythrocyte membranes. A mutation of the ChAc gene was thus likely so the diagnosis of ChAc was retained. Genetic studies for VPS13A are pending., Discussion: ChAc is an autosomal recessive disorder due to mutations of the VPS13A gene coding for chorein. Absence or late appearance of acanthocytes in ChAc has been described in a few case reports. In conclusion ChAc is a rare disorder in which the presence of acanthocytes is not mandatory. In case of doubt, chorein western blot can be useful., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Background: Models of attention-deficit/hyperactivity disorder (ADHD) classically emphasize the relevance of executive processes and, recently, reward circuits. The neural bases of reward processes have barely been explored in relation to this disorder, in contrast to extensive neuroimaging studies that examine executive functions in patients with ADHD. To our knowledge, no previous studies have analyzed the volume of the ventral striatum, a key region for reward processes in ADHD children., Methods: We used a manual region-of-interest approach to examine whether there were volumetric differences in the ventral striatum of ADHD children. Forty-two children/adolescents with ADHD (ages 6-18), and 42 healthy control subjects matched on age, gender, and handedness were selected for the study., Results: The ADHD children presented significant reductions in both right and left ventro-striatal volumes (t = 3.290, p = .001; and t = 3.486, p = .001, respectively). In addition, we found that the volume of the right ventral striatum negatively correlated with maternal ratings of hyperactivity/impulsivity (r = -.503, p = .003)., Conclusions: Our study provides neuroanatomical evidence of alterations in the ventral striatum of ADHD children. These findings coincide with previous explicative models as well as with recent reports in behavioral and functional neuroimaging studies. Furthermore, the negative correlations we observed strongly uphold the relation between the ventral striatum and symptoms of hyperactivity/impulsivity.

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous compound that is constantly present in the brain, and that exhibits neuroprotective activity. Our earlier study has suggested that 1MeTIQ may play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. It is well known that central nervous system stimulants such as: amphetamine, cocaine, phencyclidine, and selective NMDA receptor antagonists, e.g., MK-801 produce neuropsychotoxicity (psychosis, addiction) that is indistinguishable from paranoid type schizophrenia. In rodents, phencyclidine and MK-801 are often used to evoke schizophrenia-like behavioral abnormalities which are inhibited by neuroleptics. The present study was designed to further investigate potential antipsychotic properties of 1MeTIQ by using both behavioral and neurochemical studies in the rat. We investigated the influence of 1MeTIQ (25 and 50 mg/kg ip) on locomotor hyperactivity, disruptions of prepulse inhibition (PPI), and working memory impairment induced by the NMDA receptor antagonist, MK-801 (0.2-0.3 mg/kg ip). In addition in the biochemical study, we analyzed the effect of 1MeTIQ on the changes in dopamine metabolism in different brain structures and in extraneuronal release of dopamine and glutamate in the rat frontal cortex, produced by MK-801. The concentration of dopamine (DA) and its metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA), as well as the extraneuronal concentration of dopamine and glutamate were established by HPLC. MK-801 (0.25 mg/kg ip) evoked significant disruptions of PPI and working memory impairment, and co-administration of 1MeTIQ at two investigated doses of 25 and 50 mg/kg ip did not antagonize these effects. On the other hand hyperactivity evoked by MK-801 as well as a rise in dopamine metabolism in specific brain structures and glutamate release in the frontal cortex was completely antagonized by pretreatment with 1MeTIQ. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that 1MeTIQ will show efficacy in treating this condition. In conclusions, the present study suggests that 1MeTIQ, an endogenous neuroprotective compound, exhibits also antipsychotic-like efficacy in some animal tests, and may be useful in clinical practice as a psychosis-attenuating drug in schizophrenic patients. However, 1MeTIQ did not attenuate sensorimotor gating deficit or working memory impairment evoked by MK-801 which may be served as a model of negative symptoms of schizophrenia.