Abnormal cerebellar function and tremor in a mouse model for non‐manifesting partially penetrant dystonia type 6

Abstract

Loss-of-function mutations in the Thap1 gene cause partially penetrant dystonia type 6 (DYT6). r Some non-manifesting DYT6 mutation carriers have tremor and abnormal cerebellothalamo-cortical signalling. r We show that Thap1 heterozygote mice have action tremor, a reduction in cerebellar neuron number, and abnormal electrophysiological signals in the remaining neurons. r These results underscore the importance of Thap1 levels for cerebellar function. r These results uncover how cerebellar abnormalities contribute to different dystonia-associated motor symptoms.

Influence of data sampling methods on the representation of neural spiking activity in vivo

“… Neurons included are from previously published studies. 7 , 13 , 38 , 75 Significant differences are in bold italics. …”

“… 74 An example of irregularity in the form of large rate fluctuation with a much smaller concomitant increase in local variability has been observed in animal models with abnormal movements where bursts of very regular (low CV2) action potentials are interspersed by long pauses (resulting in high CV). 7 , 75 , 93 Additionally, CV and CV2 can vary from control with both measures increasing together as the cell becomes more irregular, 8 both decreasing as cell activity becomes more regular, 13 both measures differing in opposite directions, 93 or with one parameter changing while the other is stable. 7 , 94 Therefore, each parameter provides an independent and unique measurement of the definition of firing rate variability.…”

“…Animals included in the analyses are control mice from mixed genetic backgrounds unless otherwise stated. The majority of neurons included in our analyses were reported in our previous publications (nuclei neurons and Purkinje cell recordings in awake mice 7 , 8 , 13 , 94 , 105 and nuclei neurons and Purkinje cell recordings in anesthetized mice 38 , 75 ). Procedures for electrophysiologically identifying different neurons, and collecting the data from different mice, cohorts and preparations by different experimenters was consistent between studies.…”

“…In mouse models of cerebellar movement disorders, the source of cerebellar dysfunction is consistent with changes in the firing rate and/or pattern of Purkinje cell and cerebellar nuclei neuron firing. 7 , 13 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 Altered basal firing properties have also been reported in the thalamus, 11 basal ganglia, 60 and cerebral cortex 61 during abnormal movements, and during seizures. 62 , 63 The task of recording firing activity from neurons in the awake condition has many challenges and limitations, particularly in movement disorders, as the awake animal may frequently perform involuntary actions that can destabilize neural recordings.…”

“…Even in the absence of using chronic recordings or task-specific responsiveness approaches, many experimenters set a predetermined recording duration or spike number as inclusion criterion for analyses of neural firing properties. 4 , 6 , 12 , 13 Due to the opportunistic nature of these recordings, experimenters must also decide how many neurons and patients, or animals, to attempt to include in these analyses. Here, we investigate how data sampling strategies may influence the representation of firing properties of single neurons.…”