Abnormal spontaneous and harmaline-stimulated Purkinje cell activity in the awake genetically dystonic rat

The genetically dystonic rat is an autosomal recessive mutant with a movement disorder that closely resembles the generalized dystonias seen in humans. Abnormal activity of neurons within the cerebellar nuclei is critical to the dystonic rat motor syndrome. Increased glutamic acid decarboxylase activity, increased glucose utilization, and decreased muscimol binding within the cerebellar nuclei of the dystonic rat suggests that Purkinje cell firing rates are increased in these animals. However, under urethane anesthesia, Purkinje cell simple spike firing rates in dystonic rats were less than half the rates seen in normal littermates. In this study, both spontaneous and harmaline-stimulated single-unit Purkinje cell recordings were obtained from awake normal and dystonic rats. In striking contrast to previous results obtained under urethane anesthesia, there was no statistically significant difference in average Purkinje cell spontaneous simple spike frequency between dystonic and normal rats. Similar to previous studies obtained under urethane anesthesia, Purkinje cell spontaneous complex spike frequency was much lower in dystonic than in normal rats. Many Purkinje cells from dystonic rats, particularly those from the vermis or older animals, exhibited rhythmic bursting simple spike firing patterns. Cross-correlations showed that complex spikes produced less suppression of simple spikes in dystonic than in normal rats and harmaline-stimulated complex spike activity was, on average, faster and more rhythmic in normal than in dystonic rats. These findings indicate that olivocerebellar network abnormalities in the dystonic rat are not due to an inability of Purkinje cells to fire at normal rates and suggest that abnormal Purkinje cell bursting firing patterns in the dystonic rat are due to a defect in the pathway from the inferior olive to climbing fiber synapses on Purkinje cells

Inferior olive serotonin and norepinephrine levels during development in the genetically dystonie rat

The dystonic (dt) rat is an autosomal recessive mutant with a motor syndrome that shares several features with idiopathic torsion dystonia in humans. In the dt rats, marked biochemical and physiological abnormalities have been localized to the olivo-cerebellar system. At the pharmacological level, the dt rats exhibit enhanced sensitivity to the behavioral effects of serotonergic (5HT) agonists, including quipazine, a drug that activates the neurons of the inferior olive (IO). High performance liquid chromatography with electrochemical detection was used to assay 5-HT, 5-hydroxyindoleacetic acid (5HIAA), and norepinephrine (NE) in micropunches of the IO in normal and dt rats at 14, 18 and 22 days of age. Samples of the rostral frontal lobes were used as internal controls. Significant age-dependent effects were seen on 5-HT and 5-HIAA levels in the IO, but not the frontal cortex, in both groups. Although both groups reached similar 5-HT levels by postnatal day 22, a significant interaction effect between age and phenotype indicated a difference in the pattern of development. Administration of quipazine (10 mg/kg, IP) to 18-day-old normal and dt rats l h prior to sacrifice caused significant reductions in NE, 5-HIAA and the ratio of 5-HIAA to 5-HT; however, no phenotypic differences were detected. The findings do not suggest that the differential behavioral responses to 5-HT agonists seen in normal and dt rats are the result of global abnormalities in 5-HT systems, nor do they suggest the presence of presynaptic defects in the IO. The age-dependent differences in 5-HT levels in the IO may, however, indicate a developmental abnormality in the 5-HT innervation of this structure in the dt rat. Serotonin Norepinephrine Inferior olive Dystonia 5-hydroxyindoleacetic acid Quipazine. © 1993

Cerebellectomy eliminates the motor syndrome of the genetically dystonic rat

The genetically dystonic (dt) rat is a neurological mutant that displays a movement disorder characterized by repetitive twisting movements of the trunk and limbs. Previous work has identified the cerebellum of the dt rat as a site of biochemical, metabolic, and functional abnormality. In order to test the hypothesis that a cerebellar defect is critical to the expression of the motor syndrome, groups of dt rats and phenotypically normal littermates underwent cerebellectomy (CBX) at either 15 or 20 days of age. The performance of these animals on a battery of motor tasks was compared with their preoperative performance. Age-matched unoperated rats of the same phenotype and a group of dt rats with lesions in the entopeduncular nuclei (ENTO) served as controls. In dt rats. CBX permanently eliminatedall motor signs of the disease except pivoting movements without reducing overall levels of activity. In the dt rats, CBX also caused significant improvement in several tests of motor function. The ENTO group, however, showed an increase in motor signs and no improvement in motor function. The results of this study provide the first evidence that the abnormalities detected in the cerebellum of the dt rat are causally related to the motor syndrome and suggest that abnormal cerebellar output may contribute to the expression of motor signs in some human dystonias. © 1993 Academic Press. All rights reserved

Selective elimination of cerebellar output in the genetically dystonic rat

The genetically dystonic (dt) rat, an autosomal recessive mutant, exhibits a progressive motor syndrome that resembles the generalized idiopathic dystonia seen in humans. Even with supportive measures,dt rats die before reaching maturity. A total cerebellectomy that includes the dorsal portions of the lateral vestibular nuclei (dLV) eliminates the dystonic motor syndrome of thedt rats, greatly improves motor function, and prevents early death. The selective elimination of cerebellar nuclei was used to determine the cerebellar components critical to the mutant\u27s motor syndrome. Bilateral electrolytic and/or excitatory amino acid lesions of the medial cerebellar nucleus, nucleus interpositus, lateral cerebellar nucleus and dLV were created in separate groups of 15-day-olddt rats. Rats were observed for the presence of abnormal motor signs (falls, twists, clasps, pivots) and tested on several measures of motor performance (activity, climbing, righting, homing, hanging) before surgery and again on Postnatal Day 20. All nuclear lesions produced significant improvements in motor function and decreases in the frequency of abnormal motor signs. Electrolytic lesions of the dLV were associated with the greatest improvements. © 1995 Elsevier Science B.V. All rights reserved

Serotonergic modulation of eye blinks in cat and monkey

Serotonergic modulation of spontaneous and reflexive blinking was studied in four cats and one monkey. In cats, facial nucleus injections of the type-2 serotonin receptor (5-HT2) antagonist ketanserin tended to increase the latency of the first (R1) and second (R2) components of the blink reflex to supraorbital nerve stimulation. Injections of serotonin tended to increase and of ketanserin, to decrease the duration and amplitude of R2. Serotonin also produced unilateral blepharospasm and hemifacial spasm. In the monkey, the 5-HT2 agonist 2,5-dimethoxy-4-iodoamphetamine increased spontaneous blink frequency while ketanserin decreased both peak blink velocity and spontaneous blink frequency. These findings in cat and monkey indicate that serotonergic innervation of the facial nucleus has a behaviorally important role in modulation of spontaneous and reflexive blinks and suggest that dysfunction of serotonergic systems could be important to the pathophysiology of some cases of blepharospasm

Blink reflex to supraorbital nerve stimulation in the cat

Neurophysiological studies of the blink reflex to supraorbital nerve stimulation were conducted in eight alert, adult male cats. The cat, like other mammals, shows both short-latency (R1) and long-latency (R2) orbicularis oculi electromyographic (OOemg) components. Measures of OOemg latency, duration, integrated area, and maximum amplitude (MA) were obtained at a stimulus magnitude of 1.5 x R2 threshold. The mean (± SE) minimal latencies for R1 and R2 were 8.26 ± 0.85 and 22.97 ± 1.53 ms, respectively. On average, R1 MA was larger than R2 MA. R1 and R2 area measures were similar. Three stimulus paradigms were tested. In a paired-stimulus paradigm, the interstimulus interval (ISI) was randomly varied from 100 to 1200 ms. Ratios were constructed for the OOemg area and MA by dividing the test response by the conditioning response. In this paradigm, although a significant linear relationship was observed only between ISI and R2 MA, conditioning effects were noted on both R1 and R2 area and MA test responses at several ISIs. In a habituation paradigm, both R2 and R1 showed habituation at stimulus frequencies from 0.5 to 2 Hz. In a stimulus-response paradigm, stimulus magnitude was randomly varied between threshold and 2 x threshold. In this paradigm, OOemg area and MA of both R1 and R2 were linearly related to stimulus magnitude. Neither the systemically administered centrally acting α2-adrenergic antagonist yohimbine nor agonist clonidine had significant effects on blink reflex parameters, habituation, or the paired-stimulus paradigm. Overall, these results suggest that there are important similarities in the control and modulation of the R1 and R2 components of the blink reflex to supraorbital nerve stimulation in cats