“
“Dopamine neurons of the ventral midbrain fire in distinct tonic and phasic patterns (Bunney et al., 1973, Grace and Bunney, 1984a and Grace and Bunney,
1984b), providing essential signals to cortical and striatal circuits responsible for various forms of motivation, learning, salience processing, and attention (Schultz, 2007 and Bromberg-Martin et al., 2010). Convergent glutamate, GABA, and acetylcholine neurotransmitter systems, as well as multiple VE-822 clinical trial voltage-gated and calcium-activated ion channels coordinately regulate action potential firing in dopamine neurons (Shepard and Bunney, 1988, Nedergaard et al., 1993, Overton and Clark, 1997, Wolfart et al., 2001, Wolfart and Roeper, 2002 and Tepper FRAX597 solubility dmso and Lee, 2007). Mutations within several ion channels known to regulate dopamine neuron physiology have been linked to mental illnesses, including schizophrenia and bipolar disorder (Liao and Soong, 2010 and Askland et al., 2012), yet little is known about how specific channel mutations impact dopamine neuron activity. KCNN3 (SK3) shows regionally restricted expression in the brain ( Köhler et al., 1996) and is highly enriched in dopamine neurons ( Sarpal et al., 2004), where expression
is proportional to the regularity of pacemaker action potential firing ( Wolfart et al., 2001). Suppression of SK-mediated currents by the selective channel blocker apamin or the negative modulator NS8539 attenuates the refractory after-hyperpolarization
(AHP) phase of the action potential and increases spike firing irregularity in slice ( Shepard and Bunney, 1991, Wolfart et al., 2001, Bond et al., 2005 and Ji et al., 2009). Pharmacalogical inhibition of SK currents in vivo facilitates a transition from tonic to burst firing ( Waroux et al., 2005, Ji and Shepard, 2006 and Herrik et al., 2010) and promotes enhanced accumulation Carnitine dehydrogenase of dopamine metabolites ( Steketee and Kalivas, 1990), consistent with elevated dopamine release. An increase in the ratio of phasic-to-tonic dopamine signals has been proposed as an underlying contributor to the disregulation of corticostriatal information gating associated with schizophrenia (Grace, 1991). The specific behavioral impact of altering these ratios through a cell-autonomous manipulation of dopamine neuron activity patterns is not known. Intriguingly, a spontaneous mutation in KCNN3 (hSK3Δ) was identified in a patient with schizophrenia ( Bowen et al., 2001) and was later demonstrated to dominantly suppress SK-mediated currents in cell culture ( Miller et al., 2001). The extent to which this mutation influences dopamine neuron firing patterns is not known but could provide key insight into the effects of activity pattern disruption on specific dimensions of behavior associated with mental illness.