title: Compensatory T-type Ca2+ channel activity alters D2-autoreceptor responses of Substantia nigra dopamine neurons from Cav1.3 L-type Ca2+ channel KO mice.
abstract: The preferential degeneration of Substantia nigra dopamine midbrain neurons (SN DA) causes the motor-symptoms of Parkinson's disease (PD). Voltage-gated L-type calcium channels (LTCCs), especially the Cav1.3-subtype, generate an activity-related oscillatory Ca(2+) burden in SN DA neurons, contributing to their degeneration and PD. While LTCC-blockers are already in clinical trials as PD-therapy, age-dependent functional roles of Cav1.3 LTCCs in SN DA neurons remain unclear. Thus, we analysed juvenile and adult Cav1.3-deficient mice with electrophysiological and molecular techniques. To unmask compensatory effects, we compared Cav1.3 KO mice with pharmacological LTCC-inhibition. LTCC-function was not necessary for SN DA pacemaker-activity at either age, but rather contributed to their pacemaker-precision. Moreover, juvenile Cav1.3 KO but not WT mice displayed adult wildtype-like, sensitised inhibitory dopamine-D2-autoreceptor (D2-AR) responses that depended upon both, interaction of the neuronal calcium sensor NCS-1 with D2-ARs, and on voltage-gated T-type calcium channel (TTCC) activity. This functional KO-phenotype was accompanied by cell-specific up-regulation of NCS-1 and Cav3.1-TTCC mRNA. Furthermore, in wildtype we identified an age-dependent switch of TTCC-function from contributing to SN DA pacemaker-precision in juveniles to pacemaker-frequency in adults. This novel interplay of Cav1.3 L-type and Cav3.1 T-type channels, and their modulation of SN DA activity-pattern and D2-AR-sensitisation, provide new insights into flexible age- and calcium-dependent activity-control of SN DA neurons and its pharmacological modulation.
authors.affiliation: Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Poetschke
authors.affiliation: Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Dragicevic
authors.affiliation: Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Duda
authors.affiliation: Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Benkert
authors.affiliation: Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Antonios
authors.initials: A
authors.lastname: Dougalis
authors.affiliation: Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Roberta
authors.initials: R
authors.lastname: DeZio
authors.affiliation: Djavad Mowafaghian Centre for Brain and Health and Michael Smith Laboratories, University of British Columbia, V6T1Z4 Vancouver, Canada.
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
authors.affiliation: Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Joerg
authors.initials: J
authors.lastname: Striessnig
authors.affiliation: Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
mesh_terms: D000367:Age Factors; D000818:Animals; D017660:Autoreceptors / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000172:deficiency*; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D051580:Neuronal Calcium-Sensor Proteins / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism*
chemical_list: D017660:Autoreceptors; C485995:Cacna1d protein, mouse; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; C101464:frequenin calcium sensor proteins; D002118:Calcium