Altered Motor Coordination Research Articles

Altered Structure Of The Cerebellar Granule Cell Layer Of Mice Lacking Calretinin

Calcium binding proteins, such as calretinin, are abundantly expressed in distinctive patterns in the central nervous system, but their physiological functions remain poorly understood. Calretinin is highly expressed in cerebellar granule cells and calretinin deficient mice exhibit alterations in motor coordination. Using confocal microscopy, we demonstrate that the cerebellar cortex of calretinin deficient mice exhibit a significantly decreased granule cells density. Interestingly, it has been shown that the migration of granule cells is tightly associated with intracellular calcium oscillations . Therefore, we hypothesize that an alteration of these calcium oscillations in calretinin deficient mice could be involved in the observed morphological alterations. To test this assumption, we are currently developping two strategies. First, using confocal microscopy and cerebellar microexplant culture, we are studying calcium oscillations occuring during granule cell migration in the wild type control and calretinin knock-out mice. This allow us to characterize the impact of variations in calcium buffering capacity over neuronal development and on the generation of the calcium oscillations observed during the granule cell migration. On the other hand, we are developping a theoretical model to study the impact of calcium buffering modifications on the dynamics underlying the observed calcium oscillations . This dedicated computational model will shed light on the possible mechanism responsible for the modulation, by calretinin, of calcium oscillations during the granule cell migration.

A novel role for receptor like protein tyrosine phosphatase zeta in modulation of sensorimotor responses to noxious stimuli: Evidences from knockout mice studies

Receptor like protein tyrosine phosphatase zeta (RPTPz) (also known as RPTPβ or PTPξ) is a tyrosine phosphatase widely expressed in the nervous system, thought to play a role in cell–cell communication. However, knocking out RPTPz does not induce major neural abnormalities in mice. In order to better assess the potential role of RPTPz in various neural functions, we performed a comprehensive behavioural characterization of CNS/PNS functions in knockout mice (RPTPz −/−) confirming previously observed impaired working memory functions and further demonstrating an altered motor coordination. Moreover, RPTPz −/− mice displayed reduced responses to moderate thermal and tactile stimuli, both in baseline and under inflammatory conditions. These findings assign novel functional role of RPTPz in motor coordination and nociception.

Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy

Patients with hepatic encephalopathy (HE) may present different neurological alterations including impaired cognitive function and altered motor activity and coordination. HE may lead to coma and death. Many of these neurological alterations are the consequence of altered neurotransmission. Hyperammonemia is a main contributor to the alterations in neurotransmission and in neurological functions in HE. Both glutamatergic and GABAergic neurotransmission are altered in animal models of HE. We review some of these alterations, especially those alterations in glutamatergic neurotransmission responsible for some specific neurological alterations in hyperammonemia and HE: the role 1) of excessive NMDA receptors activation in death induced by acute hyperammonemia; 2) of impaired function of the glutamate-nitric oxide-cGMP pathway, associated to NMDA receptors, in cognitive impairment in chronic HE; 3) of increased extracellular glutamate and activation of metabotropic glutamate receptors in substantia nigra in hypokinesia in chronic HE. The therapeutic implications are discussed. We also review the alterations in the function of the neuronal circuits between basal ganglia-thalamus-cortex modulating motor activity and the role of sequential alterations in glutamatergic and GABAergic neurotransmission in these alterations. HE would be a consequence of altered neuronal communication due to alterations in general neurotransmission involving different neurotransmitter systems in different neurons.

Intrathecal Rosiglitazone Acts at Peroxisome Proliferator–Activated Receptor-γ to Rapidly Inhibit Neuropathic Pain in Rats

In this report, we demonstrate the transcription, expression, and DNA-binding properties of the peroxisome proliferator-activated receptor (PPAR)-gamma subtype of the peroxisome proliferator-activated nuclear receptor family to the spinal cord with real-time PCR, Western blot, and electrophoretic mobility shift assay. To test the hypothesis that activation of spinal PPAR-gamma decreases nerve injury-induced allodynia, we intrathecally administered PPAR-gamma agonists and/or antagonists in rats after transection of the tibial and common peroneal branches of the sciatic nerve. Single injection of either a natural (15-deoxy-prostaglandin J2, 15d-PGJ2) or synthetic (rosiglitazone) PPAR-gamma agonist dose-dependently decreased mechanical and cold hypersensitivity. These effects were maximal at a dose of 100 microg and peaked at approximately 60 minutes after injection, a rapid time course suggestive of transcription-independent mechanisms of action. Concurrent administration of a PPAR-gamma antagonist (bisphenol A diglycidyl ether, BADGE) reversed the effects of 15d-PGJ2 and rosiglitazone, further indicating a receptor-mediated effect. In animals without nerve injury, rosiglitazone did not alter motor coordination, von Frey threshold, or withdrawal response to a cool stimulus. Intraperitoneal and intracerebroventricular administration of PPAR-gamma agonists (100 microg) did not decrease mechanical and cold hypersensitivity, arguing against effects subsequent to diffusion from the intrathecal space. We conclude that ligand-induced activation of spinal PPAR-gamma rapidly reverses nerve injury-induced mechanical allodynia. New or currently available drugs targeted at spinal PPAR-gamma may yield important therapeutic effects for the management of neuropathic pain. PPAR-gamma receptor agonists such as rosiglitazone and pioglitazone are approved as insulin sensitizers by the United States Food and Drug Administration. We demonstrate PPAR-gamma expression in the spinal cord and report that activation of these receptors inhibits allodynia. BBB-permeant PPAR-gamma agonists may yield important therapeutic effects for the management of neuropathic pain.

Acute perinatal asphyxia impairs non-spatial memory and alters motor coordination in adult male rats

A large body of clinical evidence suggests a possible association between perinatal asphyxia and the onset of early, as well as long-term, neurological and psychiatric disorders including cognitive deficits. The present study investigated cognitive and motor function modifications in a well characterized and clinically relevant experimental rat model of human perinatal asphyxia. The results reported here show that adult rats exposed to a single (20 min) asphyctic episode at delivery displayed: (a) a deficit in non-spatial memory, assessed in a novel object recognition task; (b) an impaired motor coordination, measured by the rotarod test. On the other hand, gross motor activity and spatial memory, evaluated in both the Y maze and the Barnes maze, were not affected by perinatal asphyxia. The results of this study provide further insights into the long-term effects of perinatal asphyxia on neurobehavioural functions.

Motor activity is modulated via different neuronal circuits in rats with chronic liver failure than in normal rats

The mechanisms by which liver failure alters motor function remain unclear. It has been suggested that liver disease alters the neuronal circuit between basal ganglia and cortex that modulates motor function. Activation of group I metabotropic glutamate receptors in the nucleus accumbens (NAcc) by injecting (S)-3,5-dihydroxyphenylglycine (DHPG) activates this circuit and induces locomotion We analysed by in vivo brain microdialysis the function of the circuits that modulate motor function in rats with liver failure due to portacaval shunt (PCS). We inserted cannulae in the NAcc and microdialysis probes in the NAcc, ventral pallidum (VP), substantia nigra pars reticulata (SNr), medio-dorsal thalamus (MDT), ventro-medial thalamus (VMT) or prefrontal cortex (PFCx). We injected DHPG in the NAcc and analysed extracellular neurotransmitters concentration in these areas. The results indicate that in control rats DHPG induces locomotion by activating the 'normal' neuronal circuit: NAcc --> VP --> MDT --> PFCx. In PCS rats this circuit is not activated. In PCS rats, DHPG injection activates an 'alternative' circuit: NAcc --> SNr --> VMT --> PFCx. This circuit is not activated in control rats. DHPG injection increases dopamine in the NAcc of control but not of PCS rats, and glutamate in PCS but not in control rats. DHPG-induced increase in dopamine would activate the 'normal' neuronal circuit, while an increase in glutamate would activate the 'alternative' circuit. The identification of the mechanisms responsible for altered motor function and coordination in liver disease would allow designing treatments to improve motor function in patients with hepatic encephalopathy.

Neuromuscular and biomechanical characteristics do not vary across the menstrual cycle

Research examining the menstrual cycle and its relationship to ACL injury has focused on determining the incidence of ACL injury during the different phases of the menstrual cycle and assessing the changes in neuromuscular and biomechanical characteristics between these phases. Conflicting results warrant further investigation to determine if neuromuscular and biomechanical characteristics respond in a similar pattern to the fluctuating estradiol and progesterone. The purpose of this study was to determine if changes in the levels of estradiol and progesterone significantly altered fine motor coordination, postural stability, knee strength, and knee joint kinematics and kinetics between the menses, post-ovulatory, and mid-luteal phases of the menstrual cycle. Ten healthy and physically active females (Age: 21.4 +/- 1.4 years, Height: 1.67 +/- 0.06 m, Mass: 59.9 +/- 7.4 kg), who did not use oral contraceptives, were recruited from the local university population. Single-leg postural stability, fine motor coordination, knee strength, knee biomechanics, and serum estradiol and progesterone were assessed at the menses, post-ovulatory, and mid-luteal phases of the menstrual cycle. Levels of estradiol were significantly higher during the post-ovulatory (P = 0.016) and mid-luteal phases (P < 0.001) compared to the menses phase. Levels of progesterone were significantly lower during the menses (P < 0.001) and post-ovulatory phases (P < 0.001) compared to the mid-luteal phase. No significant differences existed between phases of the menstrual cycle for fine motor coordination (P = 0.474), postural stability (P = 0.707), hamstring - quadriceps strength ratio at 60 degrees s(-1) (P = 0.748) or 180 degrees s(-1) (P = 0.789), knee flexion excursion (P = 0.6), knee valgus excursion (P = 0.899), peak proximal tibial anterior shear force (P = 0.797), flexion moment at peak proximal tibial anterior shear force (P = 0.698), or valgus moment at peak proximal tibial anterior shear force (P = 0.924). The results of the current study suggest neuromuscular and biomechanical characteristics are not influenced by estradiol and progesterone fluctuations. All neuromuscular and biomechanical characteristics remained invariable between testing sessions despite concentration changes in estradiol and progesterone.

A possible mechanism for anxiolytic and antidepressant effects of alpha- and beta-amyrin from Protium heptaphyllum (Aubl.) March

In the present study, we examined the anxiolytic and antidepressant effects of the mixture of alpha- and beta-amyrin (AMY), pentacyclic triterpenes isolated from the stem bark resin of Protium heptaphyllum. These effects of AMY were demonstrated by the open-field, elevated-plus-maze, rota rod, forced swimming, and pentobarbital-induced sleeping time tests, in mice. In the open-field test, AMY at the doses of 10, 25 and 50 mg/kg, after intraperitoneal or oral administrations, significantly decreased the number of crossings, grooming, and rearing. All these effects were reversed by the pre-treatment with flumazenil (2.5 mg/kg, i.p.), similarly to those observed with diazepam used as a positive standard. In the elevated-plus-maze test, AMY increased the time of permanence and the number of entrances in the open arms. On the contrary, the time of permanence and the number of entrances in the closed arms were decreased. All these effects were also completely reversed by flumazenil, an antagonist of benzodiazepine receptors. In the pentobarbital-induced sleeping time test, AMY at the same doses significantly increased the animals sleeping time duration. In the rota rod test, AMY did not alter motor coordination and, thus, was devoid of effects, as related to controls. Since AMY, at the doses of 10 and 25 mg/kg, showed a sedative effect in the open field test, lower doses (2.5 and 5.0 mg/kg) were used in the forced swimming test, producing a decrease in the immobility time, similarly to that of imipramine, the positive control. The effect of AMI was greater when it was administered 15 min after imipramine (10 mg/kg). However, the antidepressant AMY effects were not altered by the previous administration of paroxetine, a selective blocker of serotonin uptake. In addition, AMY effects in the forced swimming test were totally blocked by reserpine pretreatment, a drug known to induce depletion of biogenic amines. In conclusion, the present work evidenced sedative and anxiolytic effects of AMY that might involve an action on benzodiazepine-type receptors, and also an antidepressant effect where noradrenergic mechanisms will probably play a role.

The mouse Trm1-like gene is expressed in neural tissues and plays a role in motor coordination and exploratory behaviour

Using a gene trap approach in ES cells, the novel mouse gene Trm1-like with substantial sequence homology to human C1orf25 mRNA (GenBank accession no. AF288399) was identified. Murine Trm1-like encodes a putative protein with limited similarity to N2, N2-dimethylguanosine tRNA methyltransferase ( Trm1) from other organisms, however its function is not known. The potential role of Trm1-like was investigated in a mouse mutant lacking intact Trm1-like transcripts due to integration of the gene trap vector in the first intron. Trm1-like deficient mice are viable and show no apparent anatomical defects. Behavioural tests, however, revealed significantly altered motor coordination and aberrant exploratory behaviour. LacZ activity of the trapped mouse Trm1-like gene reflects expression in various neuronal structures during embryonic development, including spinal ganglia, trigeminal nerve and ganglion, olfactory and nasopharyngeal epithelium, and nuclei of the metencephalon, thalamus and medulla oblongata. The gene is also expressed in lung, oesophagus, epiglottis, ependyma, vertebral column, spinal cord, and brown adipose tissue. Trm1- like expression persists in the adult brain with dynamically changing patterns in cortex and cerebellum. Although Trm1- like is not essential for embryonic mouse development, it may have a role in modulating postnatal neuronal functions.

Emerin-Lacking Mice Show Minimal Motor and Cardiac Dysfunctions with Nuclear-Associated Vacuoles

Emery-Dreifuss muscular dystrophy is an inherited muscular disorder clinically characterized by slowly progressive weakness affecting humero-peroneal muscles, early joint contractures, and cardiomyopathy with conduction block. The X-linked recessive form is caused by mutation in the EMD gene encoding an integral protein of the inner nuclear membrane, emerin. In this study, mutant mice lacking emerin were produced by insertion of a neomycin resistance gene into exon 6 of the coding gene. Tissues taken from mutant mice lacked emerin. The mutant mice displayed a normal growth rate indistinguishable from their littermates and were fertile. No marked muscle weakness or joint abnormalities were observed; however, rotarod test revealed altered motor coordination. Electrocardiography showed mild prolongation of atrioventricular conduction time in emerin-lacking male mice older than 40 weeks of age. Electron microscopic analysis of skeletal and cardiac muscles from emerin-lacking mice revealed small vacuoles, which mostly bordered the myonuclei. Our results suggest that emerin deficiency causes minimal motor and cardiac dysfunctions in mice with a structural fragility of myonuclei.

Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

Consumption of alcoholic beverages produces alterations in motor coordination and equilibrium that are responsible for millions of accidental deaths. Studies indicate that ethanol produces these alterations by affecting the cerebellum, a brain region involved in the control of motor systems. Purkinje neurons of the cerebellar cortex have been shown to be particularly important targets of ethanol. However, its mechanism of action at these neurons is poorly understood. We hypothesized that ethanol could modulate Purkinje neuron function by altering the excitatory input provided by the climbing fiber from the inferior olive, which evokes a powerful all-or-none response denoted as the complex spike. To test this hypothesis, we performed whole-cell patch-clamp electrophysiological and Ca2+ imaging experiments in acute slices from rat cerebella. We found that ethanol potently inhibits the late phase of the complex spike and that this effect is the result of inhibition of type-1 metabotropic glutamate receptor-dependent responses at the postsynaptic level. Moreover, ethanol inhibited climbing fiber long-term depression, a form of synaptic plasticity that also depends on activation of these metabotropic receptors. Our findings identify the climbing fiber-->Purkinje neuron synapse as an important target of ethanol in the cerebellar cortex and indicate that ethanol significantly affects cerebellar circuits even at concentrations as low as 10 mm (legal blood alcohol level in the United States is below 0.08 g/dl = 17 mm).

Reversible inactivation of the dorsal hippocampus by tetrodotoxin or lidocaine: A comparative study on cerebral functional activity and motor coordination in the rat

Reversible inactivation of the hippocampus by lidocaine or tetrodotoxin is used to investigate implications of this structure in memory processes. Crucial points related to such inactivation are the temporal and spatial extents of the blockade. We compared effects of intrahippocampal infusions of commonly-used doses of lidocaine (5 or 10 μg) or tetrodotoxin (5 or 10 ng) in rats at two post-infusion delays (5 or 30 min), using 2-deoxyglucose autoradiography to visualize local cerebral glucose metabolism, and beam-walking performance to assess motor coordination. In addition, memory retrieval was evaluated in a water maze after bilateral infusions of 10 μg lidocaine. A unilateral tetrodotoxin infusion induced dose- and time-dependent reductions of 2-deoxyglucose uptake in the vicinity of the infusion site (dorsal hippocampus: −29% to −67%) and in other ipsi- and contralateral brain regions (ventral hippocampus, lateral thalamus, cortical regions). The maximal effect was at 10 ng, at the delay of 30 min between the tetrodotoxin infusion and the 2-deoxyglucose injection. Uni- and bilateral infusions of tetrodotoxin induced dramatic motor coordination deficits. Conversely, lidocaine reduced 2-deoxyglucose uptake (−19%) in the dorsal hippocampus only at 10 μg, with weak extrahippocampal effects. Whether infused uni- or bilaterally and regardless of the dose, lidocaine did not alter motor coordination. When infused bilaterally, however, 10 μg of lidocaine impaired short-term retrieval of spatial information in a water maze. Because lidocaine i) induced a weak though significant functional blockade mainly restricted to the infusion site, ii) had no consequences on motor coordination and, nevertheless iii) altered short-term spatial memory retrieval, we conclude that acute intrahippocampal infusions of lidocaine may offer some advantages over tetrodotoxin at the doses used herein.

Altered Modulation of Motor Activity by Group I Metabotropic Glutamate Receptors in the Nucleus Accumbens in Hyperammonemic Rats

One of the neurological complications in hepatic encephalopathy is the impairment of motor coordination and function. Clinical signs of basal ganglia, cortico-spinal and cerebellar dysfunction have been commonly detected in these patients. We are studying the molecular bases of the alterations in motor coordination and function in hepatic encephalopathy. Hyperammonemia is considered the main factor responsible for the neurological alterations in patients with hepatic encephalopathy. Activation of metabotropic glutamate receptors (mGluRs) in the nucleus accumbens (NAcc) induces locomotion in rats. Asa first step in our studies on the alterations in motor co-ordination and function in hyperammonemia and hepatic encephalopathy we studied whether the control of motor function by mGluRs in the NAcc is altered in hyperammonemic rats. The locomotor activity induced by injection into the nucleus accumbens (NAcc) of DHPG, an agonist of group I mGluRs was significantly increased in hyperammonemic rats. Injection of DHPG increased extracellular dopamine but not glutamate in the NAcc of control rats. In hyperammonemic rats DHPG-induced increase in dopamine was significantly reduced, and extracellular glutamate increased 6-fold. The content of mGluR 1 but not mGluR 5, is increased in the NAcc of hyperammonemic rats. Blockade of mGluR 1 completely prevented motor and neurochemical effects induced by DHPG. These results show that modulation of both motor function and extracellular concentration of neurotransmitters by mGluRs in the NAcc is altered in hyperammonemia. This may contribute to the alterations in motor function in hepatic encephalopathy.

Pregnancy-related pelvic girdle pain (PPP), I: Terminology, clinical presentation, and prevalence.

Pregnancy-related lumbopelvic pain has puzzled medicine for a long time. The present systematic review focuses on terminology, clinical presentation, and prevalence. Numerous terms are used, as if they indicated one and the same entity. We propose "pregnancy-related pelvic girdle pain (PPP)", and "pregnancy-related low back pain (PLBP)", present evidence that the two add up to "lumbopelvic pain", and show that they are distinct entities (although underlying mechanisms may be similar). Average pain intensity during pregnancy is 50 mm on a visual analogue scale; postpartum, pain is less. During pregnancy, serious pain occurs in about 25%, and severe disability in about 8% of patients. After pregnancy, problems are serious in about 7%. The mechanisms behind disabilities remain unclear, and constitute an important research priority. Changes in muscle activity, unusual perceptions of the leg when moving it, and altered motor coordination were observed but remain poorly understood. Published prevalence for PPP and/or PLBP varies widely. Quantitative analysis was used to explain the differences. Overall, about 45% of all pregnant women and 25% of all women postpartum suffer from PPP and/or PLBP. These values decrease by about 20% if one excludes mild complaints. Strenuous work, previous low back pain, and previous PPP and/or PLBP are risk factors, and the inclusion/exclusion of high-risk subgroups influences prevalence. Of all patients, about one-half have PPP, one-third PLBP, and one-sixth both conditions combined. Overall, the literature reveals that PPP deserves serious attention from the clinical and research communities, at all times and in all countries.

Distinct roles of Galpha(q) and Galpha11 for Purkinje cell signaling and motor behavior.

G-protein-coupled metabotropic glutamate group I receptors (mGluR1s) mediate synaptic transmission and plasticity in Purkinje cells and, therefore, critically determine cerebellar motor control and learning. Purkinje cells express two members of the G-protein G(q) family, namely G(q) and G11. Although in vitro coexpression of mGluR1 with either Galpha11 or Galpha(q) produces equally well functioning signaling cascades, Galpha(q)- and Galpha11-deficient mice exhibit distinct alterations in motor coordination. By using whole-cell recordings and Ca2+ imaging in Purkinje cells, we show that Galpha(q) is required for mGluR-dependent synaptic transmission and for long-term depression (LTD). Galpha11 has no detectable contribution for synaptic transmission but also contributes to LTD. Quantitative single-cell RT-PCR analyses in Purkinje cells demonstrate a more than 10-fold stronger expression of Galpha(q) versus Galpha11. Our findings suggest an expression level-dependent action of Galpha(q) and Galpha11 for Purkinje cell signaling and assign specific roles of these two G(q) isoforms for motor coordination.

Altered Neuronal Excitability in Cerebellar Granule Cells of Mice Lacking Calretinin

Calcium-binding proteins such as calretinin are abundantly expressed in distinctive patterns in the CNS, but their physiological function remains poorly understood. Calretinin is expressed in cerebellar granule cells, which provide the major excitatory input to Purkinje cells through parallel fibers. Calretinin-deficient mice exhibit dramatic alterations in motor coordination and Purkinje cell firing recorded in vivo through unknown mechanisms. In the present study, we used patch-clamp recording techniques in acute slice preparation to investigate the effect of a null mutation of the calretinin gene on the intrinsic electroresponsiveness of cerebellar granule cells at a mature developmental stage. Calretinin-deficient granule cells exhibit faster action potentials and generate repetitive spike discharge showing an enhanced frequency increase with injected currents. These alterations disappear when 0.15 mm of the exogenous fast-calcium buffer BAPTA is infused in the cytosol to restore the calcium-buffering capacity. A proposed mathematical model demonstrates that the observed alterations of granule cell excitability can be explained by a decreased cytosolic calcium-buffering capacity resulting from the absence of calretinin. This result suggests that calcium-binding proteins modulate intrinsic neuronal excitability and may therefore play a role in information processing in the CNS.

A New Animal Model of Hereditary Cerebellar Ataxia and Male Sterility: The AMS Mouse

A novel genetic variant mouse, which exhibited ataxia and male sterility named AMS mouse, arising in autoimmune-prone MRL/lpr is described. Inheritance pattern of mutation and linkage between ams and lpr genes: The phenotype expression of the AMS trait was transmitted as autosomal recessive inheritance according to the Mendelian pedigree patterns. Analysis of the linkage between lpr and ams genes using littermates from the crosses of ams-lpr heterozygous mice indicated that the two autosomal recessive genes are inherited without linkage. Behavioral phenotype expression of the ams mutation: Qualitative observation of the spontaneous behavior and stance revealed subtle tremor of the whole body, difficulty in maintaining normal posture and moderate ataxia. The rotor rod test confirmed the presence of altered motor coordination based on the inabililty of the mutant mice to walk on the rod. Walking tracks of affected ams mutant illustrated an abnormal pattern of footfalls indicative ataxic gait. Stride lengths of steps were shorter than those of non-affected mice and the stride widths were a little bit wider when they were compared to the non-affected mice. Neuroanatomical expression of the AMS phenotype: Macroscopic examination of the brain showed a smaller cerebellum when it was compared to the age-matched unaffected mice. Microscopically, the cerebellar cortex retained its trilaminar organization and the formation of the anterior and posterior lobes, although loss of Purkinje cells (PCs) was observed throughout the Purkinje cell layer (PCL) . Anti-IP3R immunostaining of the cerebelli of 3-week old mice revealed an uneven staining of the PC and molecular layers due to profound degeneration and loss of the PCs. Examination of the time course of cellular loss in the PCL indicated that 50% of the PCs were already lost at 3 weeks of age, when the subtle manifestation of ataxia was first discernible. The cell loss accelerated very rapidly and was virtually complete at 6 weeks of age. There was no particular pattern of cell loss, rather the degeneration and loss of PCs seemed to take place in a single cell basis but the exact mechanism remains to be elucidated. The post-developmental onset of PC degeneration offers the advantage of looking at epigenetic factors that might alter the progression of the disease and therefore may help in the development of treatment strategies for human hereditary disorders. AMS phenotype expression in reproductive organs: The homozygous male and female mice were infertile. The male sterility was due to cessation of differentiation and degeneration of gametes mainly in spermatid stages after 5 weeks of age. As expected, the tubes in the epididymis appeared almost empty or contained minimal amount of degenerating sperms. In addition, there were no pathological changes in the hypothalamus, pituitary gland, Leydig and Sertoli cells indicative of a hormonal defect. These findings suggest that pretesticular causes did not contribute to the male sterility. On the other hand, histopathological examination of the ovaries showed no major changes and the ova were fertile in in vitro fertilization. Effect of ams mutation on immune system: In addition to the two major manifestations in the central nervous system and male reproductive system described above, the ams mutation was associated with a reduction of the spleen weight by about 45% when it was compared to the lpr non-homozygous mice. Immune cytological changes were also evident in the spleen. However, changes in the immune system did not result in clinically overt immunological diseases as immunodeficiency or autoimmunity, and interpreted as a minor effect of ams mutation. Conclusion: A new mutant mouse manifesting ataxia and male sterility was described. This mutant might help us understand the mechanisms of neurodegenerative processes and male sterility as well as the common genetic

Modulation of ethanol-induced motor incoordination by mouse striatal A 1 adenosinergic receptor

We have demonstrated that ethanol-induced motor incoordination is modulated by cerebellar adenosine A 1 receptor. This study represents an extension into another important brain motor area, the striatum that, unlike cerebellum, has high density of both A 1 and A 2A receptors. Direct intra-striatal micro-infusion of Ro15-4513 (0.05, 0.5, 1 ng), a partial inverse-agonist of benzodiazepine, significantly and nearly dose-dependently attenuated ethanol-induced motor incoordination indicating mediation of ethanol’s motor incoordination by striatum. Intra-striatal A 1-selective agonist N 6-cyclohexyladenosine (CHA; 1, 2, 4 ng), A 1 = A 2A non-selective agonist, 5′-N-ethylcarboxamidoadenosine (NECA; 1.5, 3, 6 ng), and A 1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 25, 50, 100 ng) dose-dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, strongly suggesting modulation by striatal adenosine A 1 receptor. Intra-striatal DPCPX significantly antagonized not only ethanol-induced motor incoordination but also its potentiation by intra-striatal CHA, R-(+)-N 6-(2-phenylisopropyladenosine) (R-PIA), or NECA. No change in motor coordination occurred after the highest dose of CHA, R-PIA, or NECA followed by saline. Similarly, the highest intra-striatal dose of Ro15-4513 or DPCPX neither altered motor coordination or locomotor activity indicating relative selectivity of interaction with ethanol. Nearly 25-fold higher dose of A 2A-selective agonist, CGS-21680, compared to CHA was necessary to produce a comparable potentiation of ethanol’s motor incoordination perhaps suggesting a lack of or less significant striatal A 2A involvement. Intra-striatal pertussis toxin (0.5 μg) pre-treatment markedly attenuated ethanol-induced motor incoordination as well as its potentiation by intra-striatal CHA. These results support that striatum is one of the brain motor areas mediating the motor impairing effects of acute ethanol and that the latter’s modulation occurs via A 1-selective receptors coupled to pertussis toxin-sensitive G proteins.

Acquisition of a runway motor learning task is impaired by a beta adrenergic antagonist in F344 rats

Performance of rats on a motor learning paradigm that has been demonstrated to be dependent upon cerebellar norepinephrine (NE) was studied in male F344 rats treated with an α 1 antagonist (prazosin), an α 2 antagonist (yohimbine) or a β noradrenergic antagonist (propranolol). The ability of propranolol-treated rats (10 mg/kg i.p. 30 min prior to daily testing) to acquire proficiency on the novel motor task was impaired while prazosin-treated rats' (0.5 mg/kg i.p. 30 min prior to daily testing) and yohimbine-treated rats' (1 mg/kg i.p. 30 min prior to daily testing) rates of acquisition of the novel motor task were not different from controls. In an attempt to distinguish between alterations in motor coordination and motor learning, additional tests of psychomotor performance were assessed for all groups of rats. These examinations included a walking test on 2.5 and 5 cm rods and speed of running on the motor task. The data indicate that drug-treated rats show no difference from controls on the above parameters. Some differences, however, were observed between propranolol and controls in the time spent in the goal box. Overall, the data are consistent with our hypothesis that the β noradrenergic receptor is involved in the ability to acquire novel motor tasks.

Impaired acquisition of novel locomotor tasks in aged and norepinephrine-depleted F344 rats

Performance of rats on a motor learning paradigm that has been demonstrated to be dependent upon cerebellar norepinephrine (NE) was studied in 20-month-old F344 rats. The behavioral task is identical to that described by Watson and McElligott: Rats are trained on a runaway consisting of aluminum pegs arranged in a regular pattern. Rats receive a water reward at either end of the runaway. Subsequent to training, rats are tested for running times on a runway with irregularly spaced rods. The ability of rats to improve their performance (decrease their running times) on this novel motor task is diminished in young rats that have received 6-hydroxydopamine lesions. Rats at 20 months of age are known to have deficits in cerebellar noradrenergic transmission; thus, the hypothesis to be tested was to determine if aged rats demonstrated performance deficits similar to young rats depleted of central stores of NE. The rate of acquisition of the task was determined by the decrease in running times with successive days of training. The ability of 20-month-old F344 rats to acquire proficiency on the novel motor task was impaired and the rate of acquisition of the novel motor task was not different from the young 6-hydroxydopamine-lesioned rats. In an attempt to distinguish between alterations in motor coordination and motor learning, additional tests of psychomotor performance were assessed for all groups of rats. These tests included a walking on 2.5- and 5-cm rods, speed of running on the motor task, and number and types of mistakes made on the motor learning task. The data indicate that none of the above-mentioned factors correlated with the ability of an individual rat to learn the novel motor task, suggesting age-related motor performance deficits may be separable from motor learning deficits. This data is consistent with our hypothesis that age-related alterations in noradrenergic function may underlie the decline in motor learning.