Vocalization deficits in mice over-expressing alpha-synuclein, a model of pre-manifest Parkinson's disease.
Communication and swallowing deficits are common in Parkinson's disease (PD). Evidence indicates that voice and speech dysfunction manifest early, prior to motor deficits typically associated with striatal dopamine loss. Unlike deficits in the extremities, cranial sensorimotor deficits are refractory to standard dopamine-related pharmacological and surgical interventions, thus the mechanisms underlying vocal deficits are unclear. Although neurotoxin models have provided some insight, they typically model nigrostriatal dopamine depletion and are therefore limited. Widespread alpha-synuclein (aSyn) pathology is common to familial and sporadic PD, and transgenic mouse models based on aSyn overexpression present a unique opportunity to explore vocalization deficits in relation to extrastriatal, nondopaminergic pathologies. Specifically, mice overexpressing human wild-type aSyn under a broad neuronal promoter (Thy1-aSyn) present early, progressive motor and nonmotor deficits starting at 2-3 months, followed by parkinsonism with dopamine loss at 14 months. We recorded ultrasonic vocalizations from Thy1-aSyn mice and wild-type (WT) controls at 2-3, 6-7, and 9 months. Thy1-aSyn mice demonstrated early, progressive vocalization deficits compared with WT. Duration and intensity of calls were significantly reduced and call profile was altered in the Thy1-aSyn mice, particularly at 2-3 months. Call rate trended toward a more drastic decrease with age in the Thy1-aSyn mice compared with WT. Alpha-synuclein pathology is present in the periaqueductal gray and may underlie the manifestation of vocalization deficits. These results indicate that aSyn overexpression can induce vocalization deficits at an early age in mice and provides a new model for studying the mechanisms underlying cranial sensorimotor deficits and treatment interventions for PD.
Department of Surgery, Division of Otolaryngology- Head & Neck Surgery, University of Wisconsin.
Laura M
LM
Grant
Department of Neurology, David Geffen School of Medicine at UCLA.
Franziska
F
Richter
Department of Integrative Biology and Physiology, UCLA.
Julie E
JE
Miller
Department of Integrative Biology and Physiology, UCLA.
Stephanie A
SA
White
National Center for Voice and Speech, University of Colorado.
Cynthia M
CM
Fox
Department of Neurology, David Geffen School of Medicine at UCLA.
Chunni
C
Zhu
Department of Neurology, David Geffen School of Medicine at UCLA.
Marie-Francoise
MF
Chesselet
Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin.
Michelle R
MR
Ciucci
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D014828:Vocalization, Animal / Q000502:physiology*; D051844:alpha-Synuclein / Q000235:genetics*
C497604:SNCA protein, human; D051844:alpha-Synuclein