Spontaneous and harmaline-stimulated Purkinje cell activity in rats with a genetic movement disorder

Stratton, SE; Lorden, JF; Le, Mays; Oltmans, Gary A.

doi:10.1523/jneurosci.08-09-03327.1988

Cited by 33 publications

(17 citation statements)

References 58 publications

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“…Dysfunctional cerebellar output is a major contributor to the generalized dystonia of the dystonic rat and lesions of the cerebellum mitigate the dystonia (LeDoux et al 1993(LeDoux et al , 1995. Cerebellar abnormalities in this rat model include decreased GABAergic activity in the cerebellar nuclei and defective climbing fiber innervation of PCs (Beales et al 1990;Brown and Lorden 1989;Lorden et al 1985;Stratton et al 1988). The oscillations in the cerebellar cortex of the tg mouse provide another example of abnormal cerebellar activity in a dystonic syndrome.…”

Section: Discussionmentioning

confidence: 99%

Low-Frequency Oscillations in the Cerebellar Cortex of the Tottering Mouse

Chen¹,

Popa²,

Wang

et al. 2009

Journal of Neurophysiology

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EJ, Ebner TJ. Low-frequency oscillations in the cerebellar cortex of the tottering mouse. J Neurophysiol 101: 234 -245, 2009. First published November 5, 2008 doi:10.1152/jn.90829.2008. The tottering mouse is an autosomal recessive disorder involving a missense mutation in the gene encoding P/Q-type voltage-gated Ca 2ϩ channels. The tottering mouse has a characteristic phenotype consisting of transient attacks of dystonia triggered by stress, caffeine, or ethanol. The neural events underlying these episodes of dystonia are unknown. Flavoprotein autofluorescence optical imaging revealed transient, low-frequency oscillations in the cerebellar cortex of anesthetized and awake tottering mice but not in wild-type mice. Analysis of the frequencies, spatial extent, and power were used to characterize the oscillations. In anesthetized mice, the dominant frequencies of the oscillations are between 0.039 and 0.078 Hz. The spontaneous oscillations in the tottering mouse organize into high power domains that propagate to neighboring cerebellar cortical regions. In the tottering mouse, the spontaneous firing of 83% (73/88) of cerebellar cortical neurons exhibit oscillations at the same low frequencies. The oscillations are reduced by removing extracellular Ca 2ϩ and blocking L-type Ca 2ϩ channels. The oscillations are likely generated intrinsically in the cerebellar cortex because they are not affected by blocking AMPA receptors or by electrical stimulation of the parallel fiber-Purkinje cell circuit. Furthermore, local application of an L-type Ca 2ϩ agonist in the tottering mouse generates oscillations with similar properties. The beam-like response evoked by parallel fiber stimulation is reduced in the tottering mouse. In the awake tottering mouse, transcranial flavoprotein imaging revealed low-frequency oscillations that are accentuated during caffeine-induced attacks of dystonia. During dystonia, oscillations are also present in the face and hindlimb electromyographic (EMG) activity that become significantly coherent with the oscillations in the cerebellar cortex. These low-frequency oscillations and associated cerebellar cortical dysfunction demonstrate a novel abnormality in the tottering mouse. These oscillations are hypothesized to be involved in the episodic movement disorder in this mouse model of episodic ataxia type 2.

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Section: Discussionmentioning

confidence: 99%

Low-Frequency Oscillations in the Cerebellar Cortex of the Tottering Mouse

Chen¹,

Popa²,

Wang

et al. 2009

Journal of Neurophysiology

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“…For our dynamic-clamp stimuli, we chose 400 inhibitory input elements because this number approximates the sum of the Purkinje cells that contact each nucleus neuron electrotonically close to its spike initiation zone. Purkinje cells in vivo show an ongoing activity with mean frequencies of 35 Hz (Savio and Tempia, 1985;Stratton et al, 1988), which we used as the mean frequency of our input elements. The interspike intervals of the input elements were generated randomly (exponential distribution).…”

Section: Methodsmentioning

confidence: 99%

“…The number and location of Purkinje cell synapses onto DCN neurons (Palkovits et al, 1977;De Zeeuw and Berrebi, 1995) and the mean rate of Purkinje cell activity (Savio and Tempia, 1985;Stratton et al, 1988) are fairly well established and were approximated by our dynamic-clamp stimuli (see Materials and Methods). The amplitude of unitary postsynaptic conductances of Purkinje cell inputs has not been determined yet.…”

Section: Increasing Input Gain Transformed a Regular Into An Irregulamentioning

confidence: 99%

“…There is ample evidence in the literature that Purkinje cells show changes in spike rate related to behavior for time periods of 10 -500 msec (Mano et al, 1991;Fortier et al, 1993;Krauzlis and Lisberger, 1996). The baseline spiking frequency in awake rats is ϳ35 Hz (Savio and Tempia, 1985;Stratton et al, 1988), which we used as the mean frequency of our inhibitory input elements for the stimuli described above. To determine how frequency changes in the inhibitory input to DCN neurons affects output spiking, we tested one set of cells (n ϭ 5) for five different inhibitory input frequencies.…”

Section: The Precision Of Spike Timing Stayed High When Synchronized mentioning

confidence: 99%

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The Control of Rate and Timing of Spikes in the Deep Cerebellar Nuclei by Inhibition

2000

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Cerebellar nucleus neurons were recorded in vitro, and dynamic clamping was used to simulate inhibitory synaptic input from Purkinje cells likely to occur in vivo. Inhibitory input patterns with varying synaptic amplitudes and synchronicity were applied to determine how spike rate and spike timing can be controlled by inhibition. The excitatory input conductance was held constant to isolate the effect of dynamic inhibitory inputs on spiking. We found that the timing of individual spikes was controlled precisely by short decreases in the inhibitory conductance that were the consequence of synchronization between many inputs. The spike rate of nucleus neurons was controlled in a linear way by the rate of inhibitory inputs. The spike rate, however, also depended strongly on the amount of synchronicity present in the inhibitory inputs. An irregular spike train similar to in vivo data resulted from applied synaptic conductances when the conductance was large enough to overcome intrinsic pacemaker currents. In this situation subthreshold fluctuations in membrane potential closely followed the time course of the combined reversal potential of excitation and inhibition. This indicates that the net synaptic driving force for realistic input levels in vivo may be small and that synaptic input may operate primarily by shunting. The accurate temporal control of output spiking by inhibitory input that can be achieved in this way in the deep cerebellar nuclei may be particularly important to allow fine temporal control of movement via inhibitory output from cerebellar cortex.Key words: cerebellum; Purkinje cell; synaptic; coding; inhibition; dynamic clamp; in vitro; whole cell; synchronizationThe final output of the cerebellum is generated by the neurons of the deep cerebellar nuclei (DCN). A major source of control over DCN neurons is derived from cerebellar cortex via GABA A -type inhibitory Purkinje cell input (Billard et al., 1993). Purkinje cell synapses provide 73% of the total synapses to DCN neurons, and almost all somatic synapses of DCN neurons are inhibitory (Palkovits et al., 1977;De Zeeuw and Berrebi, 1995). This arrangement leads to the question of how inhibitory input can control spiking in postsynaptic neurons accurately. The required accuracy of this control appears to be quite high, because the function of the cerebellum has been related to precise temporal aspects of movement control (Braitenberg, 1967;Ivry and Keele, 1989;Diener et al., 1993;Braitenberg et al., 1997;Wang et al., 1998). For example, a recent study by Timmann et al. (1999) showed that throwing a ball accurately required a temporal precision of the coordination between arm movement and finger opening of ϳ10 msec. Cerebellar patients were not able to throw accurately because the temporal precision was reduced. In the present study we investigated how the Purkinje cell projection onto the DCN might support such temporally precise control apparent from the behavioral level. Although the question of precise temporal coding of neural activity via ...

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“…The olivocerbellar network is also the site of neurophysiological irregularities including abnormal spontaneous activity from the dt rat IO, Purkinje cell layer, and DCN. 59,69,70 Single unit recordings from dt rat Purkinje neurons reveal a reduced rate of complex spiking and abnormal patterns of simple spike bursting. 71 In addition, the increase in complex spike activity normally observed in response to harmaline is absent in dt rat Purkinje cells, 60,71 which is consistent with the failure of harmaline to induce tremor in these animals.…”

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confidence: 99%

Animal models of generalized dystonia

2005

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Summary: Dystonia is a prevalent neurological disorder characterized by abnormal co-contractions of antagonistic muscle groups that produce twisting movements and abnormal postures. The disorder may be inherited, arise sporadically, or result from brain insult. Dystonia is a heterogeneous disorder because patients may exhibit focal or generalized symptoms associated with abnormalities in many brain regions including basal ganglia and cerebellum. Elucidating the pathogenic mechanisms underlying dystonia has therefore been challenging. Animal models of dystonia exhibit similar heterogeneity and are useful for understanding pathogenesis. The neurochemical and neurophysiological abnormalities in rodents with idiopathic generalized dystonia suggest that dysfunctional output from basal ganglia, cerebellum, or from multiple systems is the cause of motor dysfunction. Findings from drug-or toxininduced dystonia in rodents and nonhuman primates mirror the genetic models. The parallels between dystonia in humans and animals suggest that the models will continue to prove useful in determining pathogenesis. Furthermore, detailed characterization of the existing models of dystonia and the development of new models hold promise for the identification of novel therapeutics.

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Spontaneous and harmaline-stimulated Purkinje cell activity in rats with a genetic movement disorder

Cited by 33 publications

References 58 publications

Low-Frequency Oscillations in the Cerebellar Cortex of the Tottering Mouse

Low-Frequency Oscillations in the Cerebellar Cortex of the Tottering Mouse

The Control of Rate and Timing of Spikes in the Deep Cerebellar Nuclei by Inhibition

Animal models of generalized dystonia

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