Compensatory T-type Ca2+ channel activity alters D2-autoreceptor responses of Substantia nigra dopamine neurons from Cav1.3 L-type Ca2+ channel KO mice

Sci Rep. 2015 Sep 18:5:13688. doi: 10.1038/srep13688.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Autoreceptors / metabolism*
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / deficiency*
  • Calcium Channels, T-Type / genetics*
  • Calcium Channels, T-Type / metabolism*
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism*
  • Gene Expression Regulation
  • Male
  • Membrane Potentials
  • Mice
  • Mice, Knockout
  • Neuronal Calcium-Sensor Proteins / genetics
  • Neuronal Calcium-Sensor Proteins / metabolism
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Dopamine D2 / metabolism*
  • Substantia Nigra / metabolism*

Substances

  • Autoreceptors
  • Cacna1d protein, mouse
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Calcium Channels, T-Type
  • Neuronal Calcium-Sensor Proteins
  • Neuropeptides
  • RNA, Messenger
  • Receptors, Dopamine D2
  • frequenin calcium sensor proteins
  • Calcium