Neuronal activity regulates expression of tyrosine hydroxylase in adult mouse substantia nigra pars compacta neurons

Abstract

Dysfunctional dopaminergic (DAergic) neurotransmission between the substantia nigra pars compacta (SNc) and the dorsal striatum (the nigrostriatal pathway) causes several prominent movement disorders (e.g. the motor symptoms of Parkinson's disease, dystonias and dyskinesias). Both too much and too little DA signalling can be problematic and nigrostriatal DAergic transmission is maintained at normal levels by several homeostatic mechanisms acting over timescales of milliseconds to weeks: e.g. binding of DA to tyrosine 3-monooxygenase (EC 1.14.16.2) (tyrosine Received November 1, 2010; revised manuscript received December 13, 2010; accepted December 14, 2010. Address correspondence and reprint requests to T. D. Aumann, Florey Neuroscience Institutes, The University of Melbourne, Parkville, Victoria, Australia 3010. E-mail: tim.aumann@florey.edu.auAbbreviations used: D2R, D 2 dopamine receptor; DA, dopamine; EGF, epidermal growth factor; FGF, fibroblast growth factor; GDNF, glial cellderived neurotrophic factor; GFP, green fluorescent protein; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; RRF, retrorubral field; SDS, sodium dodecyl sulfate; SK, small-conductance, Ca 2+ -activated potassium; SNc, substantia nigra pars compacta; TH, tyrosine hydroxylase; TTX, tetrodotoxin; VTA, ventral tegmental area. AbstractStriatal delivery of dopamine (DA) by midbrain substantia nigra pars compacta (SNc) neurons is vital for motor control and its depletion causes the motor symptoms of Parkinson's disease. While membrane potential changes or neuronal activity regulates tyrosine hydroxylase (TH, the rate limiting enzyme in catecholamine synthesis) expression in other catecholaminergic cells, it is not known whether the same occurs in adult SNc neurons. We administered drugs known to alter neuronal activity to mouse SNc DAergic neurons in various experimental preparations and measured changes in their TH expression. In cultured midbrain neurons, blockade of action potentials with 1 lM tetrodotoxin decreased TH expression beginning around 20 h later (as measured in real time by green fluorescent protein (GFP) expression driven off TH promoter activity). By contrast, partial blockade of small-conductance, Ca 2+ -activated potassium channels with 300 nM apamin increased TH mRNA and protein between 12 and 24 h later in slices of adult midbrain. Twoweek infusions of 300 nM apamin directly to the adult mouse midbrain in vivo also increased TH expression in SNc neurons, measured immunohistochemically. Paradoxically, the number of TH immunoreactive (TH+) SNc neurons decreased in these animals. Similar in vivo infusions of drugs affecting other ion-channels and receptors (L-type voltage-activated Ca 2+ channels, GABA A receptors, high K + , DA receptors) also increased or decreased cellular TH immunoreactivity but decreased or increased, respectively, the number of TH+ cells in SNc. We conclude that in adult SNc neurons: (i) TH expression is activity-dependent and begins to change 20 h following sustained chang...

Activity-Dependent Regulation of the Dopamine Phenotype in the Adult Substantia Nigra: Prospects for Treating Parkinson's Disease

“…278 intraventricular administration of a GABA A receptor agonist (Soriano et al 1997, Yamada et al 1996; SNc TH mRNA is elevated followed systemic administration of nicotine or α-7 nicotinic acetylcholine receptor agonists (Serova & Sabban 2002); and we recently reported that the number of SNc TH+ cells in adult mice can be increased or decreased by direct brain infusions of drugs targeting SNc neuronal activity (Aumann et al 2011, Aumann et al 2008. These data are consistent with the possibility that the DA phenotype of adult SNc neurons can be gained or lost in an activity-dependent way.…”

“…replenishing SNc DA cells by DA phenotype recruitment). We also note that the doses of riluzole used so far in clinical trials for PD have all been relatively low (around 3μM) rather than the 30μM, which we have shown increases the number of SNc TH+ cells in normal mice (Aumann et al 2011). Therefore, any restorative benefit of riluzole through DA phenotype recruitment may have been missed.…”

“…The number of SNc TH+ cells in normal adult mice increased by ~500 following a 2 week infusion of 100μM 1-EBIO (or 30μM riluzole) into midbrain (Aumann et al 2008, Aumann et al 2011. To examine whether midbrain 1-EBIO infusion can also increase SNc TH+ cells in a PD model, we repeated this in adult mice with prior depletion of TH+ SNc cells by 6-OHDA.…”

“…voltageactivated Na+, glutamate receptors and SK channels). It activates SK channels at concentrations ≥3μM (Cao et al 2002, Grunnet et al 2001) and at 30μM (direct injection) it increases the number of TH+ SNc cells in normal mice (Aumann et al 2011). We therefore tested its ability to increase the number of TH+ SNc in the PD model.…”

“…While infusion of SK channel agonists (1-EBIO or riluzole) into the normal adult mouse SNc recruited ~500 more TH+ SNc cells (Aumann et al 2008, Aumann et al 2011, infusion of the D2 DA receptor agonist quinpirole into the normal adult mouse striatum was far more potent in this respect; recruiting ~3000 new TH+ SNc cells (Aumann et al 2011). We therefore examined the behavioral and cellular effects of striatal quinpirole infusion in 6-OHDA-lesioned rats.…”