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

Abstract

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.

Selective and Sustained α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Activation in Cerebellum Induces Dystonia in Mice

“…Similar to the imaging studies in patients, abnormal cerebellar function is observed in genetic mouse and rat models of dystonia (LeDoux and Lorden, 2002;Chen et al, 2009;Zhang et al, 2011). Indeed, an increase in metabolic activity in the cerebellum is observed in mouse models of DYT1 dystonia (Ulug et al, 2011;Zhao et al, 2011), similar to imaging studies in DYT1 patients.…”

Abnormal cytoplasmic calcium dynamics in central neurons of a dystonia mouse model

“…The [Ca 2+ ] c plays important roles in controlling neuronal excitability, synaptic plasticity and gene activation, and its dysregulation is associated with a variety of neurological disorders including epilepsy [28], Huntington's disease [21] and Alzheimer's disease [43]. Ca 2+ overload could potentially lead to neuronal dysfunction in the context of dystonia In support of this notion, in vivo administration of L-type Ca 2+ channel agonists or caffeine induce dystonia-like movements in rodents [6,7,17]. Additionally, a recent study demonstrated that Ca 2+ regulation in the peripheral neurons is abnormal in dystonia musculorum, an autosomal-recessive neurodegenerative disease in mouse that is characterized by progressive ataxia and sensory neuropathy [33].…”

Motor dysfunction in the tottering mouse is linked to cerebellar spontaneous low frequency oscillations revealed by flavoprotein autofluorescence optical imaging

“…Details of animal preparation and experimental setup have been described in previous publications 24,26,27 . For some experiments mice were anesthetized by intramuscular injection of a cocktail of ketamine (60 mg/kg), xylazine (3 mg/kg) and acepromazine (1.2 mg/kg), placed in a stereotaxic frame, mechanically ventilated and body temperature feedback-regulated.…”

“…Imaging flavoprotein autofluorescence used a band pass excitation filter (455 ± 35 nm), an extended reflectance dichroic mirror (500 nm), and a > 515 nm long pass emission filter 24 . Additional imaging procedures for the awake mouse were described in a previous publication 27 . Caffeine (10-15 mg/kg, I.P.)…”

“…Therefore, flavoprotein optical imaging has the potential to identify activity changes across a surface that are may be difficult to detect with conventional electrophysiological techniques. In this study we describe how flavoprotein imaging allowed the visualization of spontaneous oscillations in the cerebellar cortex that provides new insights into episodic nervous system dysfunction 27 . Together with the results from electrophysiological and behavioral experiments, it provides a mechanism for the episodic motor dysfunction in the tg mice and may also provide insight to other episodic neurological disorders.…”