title: Subthalamic lesion or levodopa treatment rescues giant GABAergic currents of PINK1-deficient striatum.
abstract: Cellular electrophysiological signatures of Parkinson's disease described in the pharmacological 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease include spontaneous repetitive giant GABAergic currents in a subpopulation of striatal medium spiny neurons (MSNs), and spontaneous rhythmic bursts of spikes generated by subthalamic nucleus (STN) neurons. We investigated whether similar signatures are present in Pink1(-/-) mice, a genetic rodent model of the PARK6 variant of Parkinson's disease. Although 9- to 24-month-old Pink1(-/-) mice show reduced striatal dopamine content and release, and impaired spontaneous locomotion, the relevance of this model to Parkinson's disease has been questioned because mesencephalic dopaminergic neurons do not degenerate during the mouse lifespan. We show that 75% of the MSNs of 5- to 7-month-old Pink1(-/-) mice exhibit giant GABAergic currents, occurring either singly or in bursts (at 40 Hz), rather than the low-frequency (2 Hz), low-amplitude, tonic GABAergic drive common to wild-type MSNs of the same age. STN neurons from 5- to 7-month-old Pink1(-/-) mice spontaneously generated bursts of spikes instead of the control tonic drive. Chronic kainic acid lesion of the STN or chronic levodopa treatment reliably suppressed the giant GABAergic currents of MSNs after 1 month and replaced them with the control tonic activity. The similarity between the in vitro resting states of Pink1 MSNs and those of fully dopamine (DA)-depleted MSNs of 6-OHDA-treated mice, together with the beneficial effect of levodopa treatment, strongly suggest that dysfunction of mesencephalic dopaminergic neurons in Pink1(-/-) mice is more severe than expected. The beneficial effect of the STN lesion also suggests that pathological STN activity strongly influences striatal networks in Pink1(-/-) mice.
authors.affiliation: Institut de Neurobiologie de la Méditerranée UMR 901, Inserm and Aix Marseille University, 13009 Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dehorter
authors.forename: Natalia
authors.initials: N
authors.lastname: Lozovaya
authors.forename: B Julius
authors.initials: BJ
authors.lastname: Mdzomba
authors.forename: François J
authors.initials: FJ
authors.lastname: Michel
authors.forename: Catherine
authors.initials: C
authors.lastname: Lopez
authors.forename: Vera
authors.initials: V
authors.lastname: Tsintsadze
authors.forename: Timur
authors.initials: T
authors.lastname: Tsintsadze
authors.forename: Michael
authors.initials: M
authors.lastname: Klinkenberg
authors.forename: Suzanna
authors.initials: S
authors.lastname: Gispert
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.forename: Constance
authors.initials: C
authors.lastname: Hammond
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology; D004553:Electric Conductivity; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000633:toxicity; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics; D020531:Subthalamic Nucleus / Q000187:drug effects* / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000978:Antiparkinson Agents; D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D007980:Levodopa; D011494:Protein Kinases; D005680:gamma-Aminobutyric Acid; D000099202:PTEN-Induced Putative Kinase