EMG analysis of harmaline-induced tremor in normal and three strains of mutant mice with Purkinje cell degeneration and the role of the inferior olive.

1. The effects of intraperitoneal injections of 10 mg/kg harmaline were tested in normal mice and three strains of cerebellar mutant mice with Purkinje cell degeneration. Ten normal (wild-type) mice (+/+), as well as five lurcher (lc/+), six nervous (nr/nr), and eight Purkinje cell degeneration (pcd/pcd) mutants were implanted with chronic electromyogram (EMG) electrodes in the hamstring and quadriceps muscle groups of the right hindlimb. 2. EMGs were recorded in each of the mice during spontaneous activity before and after intraperitoneal injections of 0.3 ml harmaline (10 mg/kg). Spectral analysis was used to quantify the amplitude and frequency of tremor found in the EMGs after harmaline administration. Normal mice responded to harmaline with strong, continuous 11- to 14-Hz tremor. Mutants from the pcd/pcd strain also reacted with continuous tremor, but of lower amplitude and frequency. In contrast, nr/nr mutants exhibited intermittent paroxysmal tremor lasting for only a few seconds, and lc/+ mutants showed no evidence of tremor whatsoever. 3. In order to detect covert tremor that was possibly not revealed by focal intramuscular EMG recordings, several mutant and normal mice were also tested on a suspended platform to which an accelerometer was attached. The results confirmed the findings from EMG recordings. 4. An incidental observation made during the course of this study was that harmaline tremor disappeared from the normal mouse during swimming and reappeared when the animal was withdrawn from the water. 5. Although Purkinje cells appeared to increase both the depth of modulation and the frequency of tremor, the inhibitory action of the cerebellar cortex does not seem to be essential for the generation of tremor. 6. Parasagittal cerebellar sections of the normal, wild-type mice and the three strains of cerebellar mutant mice of various ages were stained with cresyl violet and examined for Purkinje cell degeneration. Purkinje cell degeneration was found to be complete in the pcd/pcd and lc/+ strains. Although an initial examination of parasagittal sections of the nr/nr strain failed to find any surviving Purkinje cells, further examination of sections cut in the coronal plane revealed small clusters of Purkinje cells in the vermal area of the posterior lobe. 7. The retrograde transport of wheat-germ-agglutinin-conjugated horseradish peroxidase (WGA-HRP) pressure-injected into the cerebellar cortex was used to study the olivocerebellar projections in the wild-type mice and the three strains of cerebellar mutant mice.(ABSTRACT TRUNCATED AT 400 WORDS)

[1]  S. Nakatani,et al.  Effect of harmaline in monkeys with central nervous system lesions. , 1970, Experimental neurology.

[2]  C. Sotelo,et al.  Cerebellar mutations affecting the postnatal survival of Purkinje cells in the mouse disclose a longitudinal pattern of differentially sensitive cells. , 1987, Developmental biology.

[3]  Y. Lamarre,et al.  Rhythmic activity induced by harmaline in the olivo-cerebello-bulbar system of the cat. , 1973, Brain research.

[4]  K. Caddy,et al.  Structural and quantitative studies on the normal C3H and Lurcher mutant mouse. , 1979, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[5]  T L Sourkes,et al.  Striatal amines, experimental tremor and the effect of harmaline in the monkey. , 1966, Brain : a journal of neurology.

[6]  E. Mugnaini,et al.  Origins of GABAergic Inputs to the Inferior Olive , 1989 .

[7]  A. Ahmed,et al.  The analysis of drug-induced tremor in mice. , 1959, British journal of pharmacology and chemotherapy.

[8]  J. Courville,et al.  Origin and trajectory of the cerebello-olivary projection: An experimental study with radioactive and fluorescent tracers in the cat , 1987, Neuroscience.

[9]  Y. Lamarre,et al.  Harmaline-induced rhythmic acitivity of alpha and gamma motoneurons in the cat. , 1973, Brain research.

[10]  K. Herrup,et al.  Interaction of granule, Purkinje and inferior olivary neurons in lurcher chimeric mice. II. Granule cell death , 1982, Brain Research.

[11]  J. Lorden,et al.  Decreased cerebellar 3',5'-cyclic guanosine monophosphate levels and insensitivity to harmaline in the genetically dystonic rat (dt) , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[12]  R. Llinás,et al.  The Functional Organization of the Olivo‐Cerebellar System as Examined by Multiple Purkinje Cell Recordings , 1989, The European journal of neuroscience.

[13]  Doris B. Wilson,et al.  Cerebellar histogenesis in the lurcher (Lc) mutant mouse , 1977, The Journal of comparative neurology.

[14]  K. Herrup,et al.  Interaction of granule, Purkinje and inferior olivary neurons in lurcher chimaeric mice. I. Qualitative studies. , 1982, Journal of embryology and experimental morphology.

[15]  J. Heckroth Quantitative morphological analysis of the cerebellar nuclei in normal and lurcher mutant mice. I. Morphology and cell number , 1994, The Journal of comparative neurology.

[16]  J. F. Lorden,et al.  Effect of harmaline on cells of the inferior olive in the absence of tremor: Differential response of genetically dystonic and harmaline-tolerant rats , 1991, Neuroscience.

[17]  R. J. Mullen,et al.  Purkinje cell degeneration, a new neurological mutation in the mouse. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Heckroth,et al.  A quantitative morphological analysis of the cerebellar nuclei in normal and lurcher mutant mice. II. Volumetric changes in cytological components , 1994, The Journal of comparative neurology.

[19]  M. Mesulam,et al.  Tetramethyl benzidine for horseradish peroxidase neurohistochemistry: a non-carcinogenic blue reaction product with superior sensitivity for visualizing neural afferents and efferents. , 1978, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[20]  Y. Lamarre,et al.  Harmaline-induced rhythmic activity of cerebellar and lower brain stem neurons. , 1971, Brain research.

[21]  C. Sotelo,et al.  Localization of glutamic‐acid‐decarboxylase‐immunoreactive axon terminals in the inferior olive of the rat, with special emphasis on anatomical relations between GABAergic synapses and dendrodendritic gap junctions , 1986, The Journal of comparative neurology.

[22]  D. Bose,et al.  A study of the role of brain catecholamines in drug induced tremor. , 1967, British journal of pharmacology and chemotherapy.

[23]  Y. Lamarre,et al.  Effects produced by local applications of harmaline in the inferior olive. , 1975, Canadian journal of physiology and pharmacology.

[24]  C. Sotelo,et al.  Non-Purkinje cell GABAergic innervation of the deep cerebellar nuclei: A quantitative immunocytochemical study in C57BL and in Purkinje cell degeneration mutant mice , 1986, Brain Research.

[25]  R. Sidman,et al.  'nervous', A new mutant mouse with cerebellar disease. Les mutants pathologiques chez l'animal (colloq. Internat. Cnrs no. , 1969 .

[26]  L. Eisenman,et al.  Olivary morphology and olivocerebellar topography in adult lurcher mutant mice , 1991, The Journal of comparative neurology.