SK2 and SK3 expression differentially affect firing frequency and precision in dopamine neurons

The firing properties of dopamine (DA) neurons in the substantia nigra (SN) pars compacta are strongly influenced by the activity of apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) channels. Of the three SK channel genes expressed in central neurons, only SK3 expression has been identified in DA neurons. The present findings show that SK2 was also expressed in DA neurons. Immuno-electron microscopy (iEM) showed that SK2 was primarily expressed in the distal dendrites, while SK3 was heavily expressed in the soma and, to a lesser extent, throughout the dendritic arbor. Electrophysiological recordings of the effects of the SK channel blocker apamin on DA neurons from wild type and SK(-/-) mice show that SK2-containing channels contributed to the precision of action potential (AP) timing, while SK3-containing channels influenced AP frequency. The expression of SK2 in DA neurons may endow distinct signaling and subcellular localization to SK2-containing channels.

[1]  B. Bunney,et al.  Repetitive firing properties of putative dopamine-containing neurons in vitro: regulation by an apamin-sensitive Ca2+-activated K+ conductance , 2004, Experimental Brain Research.

[2]  J. Wickens,et al.  Research review: dopamine transfer deficit: a neurobiological theory of altered reinforcement mechanisms in ADHD. , 2008, Journal of child psychology and psychiatry, and allied disciplines.

[3]  F. Gonon Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry , 1988, Neuroscience.

[4]  A. Grace,et al.  Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[5]  K. Rajewsky,et al.  A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. , 1995, Nucleic acids research.

[6]  A. Nieoullon Dopamine and the regulation of cognition and attention , 2002, Progress in Neurobiology.

[7]  D. James Surmeier,et al.  ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease , 2007, Nature.

[8]  P. Pedarzani,et al.  Domain Analysis of the Calcium-activated Potassium Channel SK1 from Rat Brain , 2004, Journal of Biological Chemistry.

[9]  N. Marrion,et al.  Small-Conductance, Calcium-Activated Potassium Channels from Mammalian Brain , 1996, Science.

[10]  A. Grace,et al.  The dopamine system and the pathophysiology of schizophrenia: a basic science perspective. , 2007, International review of neurobiology.

[11]  N. Marrion,et al.  Crucial role of a shared extracellular loop in apamin sensitivity and maintenance of pore shape of small-conductance calcium-activated potassium (SK) channels , 2011, Proceedings of the National Academy of Sciences.

[12]  K. Jellinger,et al.  Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. , 1973, Journal of the neurological sciences.

[13]  I. Engberg,et al.  Nifedipine‐ and omega‐conotoxin‐sensitive Ca2+ conductances in guinea‐pig substantia nigra pars compacta neurones. , 1993, The Journal of physiology.

[14]  Masahiko Watanabe,et al.  SK2 channel plasticity contributes to LTP at Schaffer collateral–CA1 synapses , 2008, Nature Neuroscience.

[15]  W. Newsome,et al.  The temporal precision of reward prediction in dopamine neurons , 2008, Nature Neuroscience.

[16]  John P. Horn,et al.  Cav1.3 Channel Voltage Dependence, Not Ca2+ Selectivity, Drives Pacemaker Activity and Amplifies Bursts in Nigral Dopamine Neurons , 2009, The Journal of Neuroscience.

[17]  B. Bunney,et al.  Effects of apamin on the discharge properties of putative dopamine-containing neurons in vitro , 1988, Brain Research.

[18]  Jochen Roeper,et al.  Differential Expression of the Small-Conductance, Calcium-Activated Potassium Channel SK3 Is Critical for Pacemaker Control in Dopaminergic Midbrain Neurons , 2001, The Journal of Neuroscience.

[19]  J J Jack,et al.  Electrophysiology of dopaminergic and non‐dopaminergic neurones of the guinea‐pig substantia nigra pars compacta in vitro. , 1991, The Journal of physiology.

[20]  T. Kita,et al.  Electrical membrane properties of rat substantia nigra compacta neurons in an in vitro slice preparation , 1986, Brain Research.

[21]  C. Wilson,et al.  Coupled oscillator model of the dopaminergic neuron of the substantia nigra. , 2000, Journal of neurophysiology.

[22]  R. Luján,et al.  Molecular and Cellular Diversity of Neuronal G-Protein-Gated Potassium Channels , 2005, The Journal of Neuroscience.

[23]  F. Gonon,et al.  Regulation of dopamine release by impulse flow and by autoreceptors as studied by in vivo voltammetry in the rat striatum , 1985, Neuroscience.

[24]  A. Grace,et al.  Intracellular and extracellular electrophysiology of nigral dopaminergic neurons—1. Identification and characterization , 1983, Neuroscience.

[25]  A. Janowsky,et al.  Domains Responsible for Constitutive and Ca2+-Dependent Interactions between Calmodulin and Small Conductance Ca2+-Activated Potassium Channels , 1999, The Journal of Neuroscience.

[26]  R. Stackman,et al.  Small Conductance Ca2+-Activated K+ Channel Knock-Out Mice Reveal the Identity of Calcium-Dependent Afterhyperpolarization Currents , 2004, The Journal of Neuroscience.

[27]  N. Mercuri,et al.  Two cell types in rat substantia nigra zona compacta distinguished by membrane properties and the actions of dopamine and opioids , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  N. Verhoeff Radiotracer imaging of dopaminergic transmission in neuropsychiatric disorders , 1999, Psychopharmacology.

[29]  D. G. Haylett,et al.  Small Conductance Ca2+‐Activated K+ Channels Formed by the Expression of Rat SK1 and SK2 Genes in HEK 293 Cells , 2003, The Journal of physiology.

[30]  Carmen C. Canavier,et al.  Regulation of firing frequency in a computational model of a midbrain dopaminergic neuron , 2010, Journal of Computational Neuroscience.

[31]  D. Jane,et al.  Allosteric Block of KCa2 Channels by Apamin* , 2010, The Journal of Biological Chemistry.

[32]  Masahiko Watanabe,et al.  T-type Ca2+ channels, SK2 channels and SERCAs gate sleep-related oscillations in thalamic dendrites , 2008, Nature Neuroscience.

[33]  K. Chergui,et al.  Nonlinear relationship between impulse flow, dopamine release and dopamine elimination in the rat brainin vivo , 1994, Neuroscience.

[34]  T. Strassmaier,et al.  A Novel Isoform of SK2 Assembles with Other SK Subunits in Mouse Brain* , 2005, Journal of Biological Chemistry.

[35]  W. Schultz Getting Formal with Dopamine and Reward , 2002, Neuron.

[36]  H X Ping,et al.  Apamin‐sensitive Ca2+-activated K+ channels regulate pacemaker activity in nigral dopamine neurons , 1996, Neuroreport.