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 Ca2+ 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.

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

“…; Poetschke et al . ). SN DA neurons are able to compensate pharmacological LTCC block as well as germline loss of Cav1.3 LTCCs [Cav1.3 KO mice (Platzer et al .…”

“…; Poetschke et al . ). HCN channels (built by HCN2‐4) facilitate SN DA pacemaker generation and its frequency (Franz et al .…”

“…TTCCs seem to have similar bidirectional functions in SN DA neurons as they not only stimulate but also inhibit pacemaker activity via stimulation of potassium channels: Cav3.1 channels can also sensitize Ca 2+ ‐ and NCS‐1 dependent D2‐AR/GIRK2 signaling (Poetschke et al . ). Additionally, TTCCs can functionally couple and activate Ca 2+ ‐stimulated A‐type K + channels (An et al .…”

“…Cav3.1 TTCCs stabilize SN DA pacemaker frequency and its precision in an age‐dependent manner (Poetschke et al . ), most likely by functional coupling to Ca 2+ sensitive small conductance potassium channels (SK3), and thereby shaping SN DA action potential after‐hyperpolarization (Wolfart et al . ; Wolfart and Roeper ; Stocker ; Bond et al .…”

Regulation of the Expression of the Psychiatric Risk Gene <b><i>Cacna1c</i></b> during Associative Learning

“…These data may indicate a specific role for Ca v 1.3 in fear memory formation. However, these models show compensatory adaptations in activity-dependent neuronal signalling [49, 51], which make these data difficult to interpret. The role of Ca v 1.2 with associative memory processing is indicated in a gain-of-function model that shows enhanced cued and contextual fear memory via altered consolidation, strengthening and/or extinction [52].…”