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

Abstract

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study was that harmaline tremor disappeared from the normal mouse during swimming and reappeared when the animal was withdrawn from the water. 5.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)

The Olivocerebellar Projection Mediates Ibogaine-Induced Degeneration of Purkinje Cells: A Model of Indirect, Trans-Synaptic Excitotoxicity

“…Harmaline-treated animals demonstrate synchronous, rhythmic bursts of activity (8 -12 Hz) throughout the spinocerebellar system, including inferior olive, Purkinje cells, deep cerebellar nuclei, reticular formation, and motoneurons (Lamarre and Mercier, 1971;Lamarre and Weiss, 1973;Llinás and Volkind, 1973). Bursts of rhythmic neuronal activity are time-locked to the harmaline-induced tremor, as assessed by electromyographic recording (De Montigny and Lamarre, 1973;Milner et al, 1995). These data indicate that the tremor is induced by rhythmic activation of motoneurons attributable to entrainment of brainstem descending pathways by the olivocerebellar rhythm.…”

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

“…The β-carboline alkaloid tremor shares many features with ET. These include several of the principal clinical features (e.g., tremor frequency and electromyographic characteristics of the tremor) and drugresponse characteristics (pharmacological responsiveness to benzodiazepines, alcohol, and barbiturates) (Cross et al, 1993;Fuentes and Longo, 1971;Milner et al, 1995;Rappaport et al, 1984;Sinton et al, 1989;Trouvin et al, 1987). Also, underlying brain changes are similar.…”

“…Changes, including neuronal loss, have been shown to occur in the ET cerebellum (Axelrad JE, 2007 In Press; Louis et al, 2002a;Louis et al, 2004;Louis et al, 2006a;Louis et al, 2006b;Pagan et al, 2003;Shill H, 2007). Similarly, β-carboline alkaloids produce toxic damage with significant loss of cerebellar Purkinje cells (Du et al, 1997;Milner et al, 1995;O'Hearn and Molliver, 1997;Robertson, 1980;Sinton et al, 1989). While β-carboline alkaloids are produced endogenously in the human body (Gearhart et al, 2000;Wakabayashi et al, 1997), one study estimated that dietary sources were fifty times greater than endogenous sources (Pfau and Skog, 2004).…”

Blood harmane concentrations and dietary protein consumption in essential tremor

“…12,13 BCA-induced tremor shares many features with ET including its principal clinical features, drug-response characteristics, [14][15][16][17][18][19] and underlying brain changes (cerebellar changes have been noted in physiologic and imaging studies of patients with ET; similarly, BCAs damage olivary-cerebellar pathways). 10,14,18,[20][21][22][23] The etiology of ET is poorly understood 24 and a better understanding of disease etiology and mechanisms has the potential to modify or prevent a disorder that affects as much as 4% of the adult population. 25 We previously demonstrated that blood concentrations of the BCA harmane were elevated in patients with ET vs controls.…”