Aktuelle Neurologie 2005; 32 - A13
DOI: 10.1055/s-2005-916300

KATP channels control the differential vulnerability of dopaminergic midbrain neurons in a chronic MPTP-model of Parkinson's disease

B Liss 1, O Haeckel 1, J Wildmann 1, T Miki 2, S Seino 2, J Roeper 1
  • 1Department of Physiology, Philipps University Marburg, Marburg, Germany
  • 2Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan

The selective and progressive degeneration of dopaminergic (DA) midbrain neurons, in particular within the substantia nigra (SN), is a hallmark of Parkinson's disease (PD) and its animal models. DA neurons in the neighbouring ventral tegmental area (VTA) are significantly less affected. The molecular mechanisms for this differential vulnerability of DA subpopulations are unknown. We have previously shown that acute inhibition of the mitochondrial complex I – in in vitro mouse brain slices – selectively inhibited the electrical activity of a subpopulation of DA neurons. These responsive DA neurons expressed a particular type of ATP-sensitive potassium (KATP) channel, comprised of the pore-forming subunit Kir6.2 and the regulatory subunit SUR1. We have now analyzed Kir6.2 knockout (KO) mice, to directly assess the role of KATP channels for differential vulnerability of DA neurons. To investigate the pathophysiological role of K-ATP channels within distinct DA subpopulations, we combined in vitro patch-clamp experiments and RT-PCR of individual, retrogradly identified mesostriatal SN and mesolimbic VTA DA neurons in adult mice. In control but not in Kir6.2 KO mice, Kir6.2/SUR1-mediated KATP channels were selectively and tonically activated by the complex I blockers MPP+ (10µM) or rotenone (100nM). Moreover, the parkinson-inducing toxins activated KATP channels only in highly vulnerable mesostriatal SN DA neurons but not in more resistant mesolimbic VTA DA neurons. To analyse the role of KATP channels in vivo, we applied a chronic low-dose MPTP PD-model to Kir6.2 KO and control mice of the same genetic background. Stereological analysis of control mice revealed an MPTP-induced loss of tyrosine-hydroxylase (TH)-positive neurons in the SN of about 50%, and in the VTA of about 25%. Inactivation of the Kir6.2 gene did not significantly alter the MPTP-induced cell-loss within the VTA, but resulted in a complete and selective rescue of the SN DA neurons. These results demonstrate that Kir6.2-mediated K-ATP channels control the differential vulnerability of DA midbrain neurons to degenerative triggers, as their presence dramatically increased the vulnerability of DA SN but not VTA neurons. Thus, contrary to the protective role of KATP channel activation during acute metabolic challenges like ischemia, sustained KATP channel activation in DA neurons -in response to chronic exposure to complex I inhibitors or other forms of metabolic stress- promotes loss of neuronal activity and cell death. These findings suggest KATP channel inhibition as a novel therapeutic strategy for PD.