Contributions of KCNQ2/3 channels to medium spiny neuron excitability and cocaine reward - PROJECT SUMMARY
Substance use disorder is a multidimensional neuropsychiatric disease increasing in prevalence across the
United States despite increased awareness and substantial leaps in treatment approaches. Unfortunately, these
treatments commonly fail due to strongly encoded drug-associations, often resulting in relapse. Drugs of abuse,
such as cocaine, act on the mesolimbic dopamine system to increase dopaminergic transmission in the nucleus
accumbens (NAc), a key brain region important for reward processing. Medium spiny neurons (MSNs) within the
NAc are responsive to increases in dopamine transmission. Importantly, MSNs do not generate spontaneous
action potentials so changes in excitability are dependent on dopaminergic input, in addition to input from other
projecting areas. When studying MSNs in relation to substance abuse, there is substantial evidence
demonstrating MSNs increase their excitability following cocaine exposure or dopamine stimulation. However,
very little research has examined why this happens and how voltage-gated ion channels in the NAc are
implicated in cocaine-induced physiological and behavioral plasticity. My preliminary data suggests a role for
KCNQ2/3, m-current, potassium channels in MSN excitability and the rewarding effects of cocaine. Although
pharmacological manipulation of KCNQ2/3 channels decreases drug seeking behaviors and KCNQ2/3 channels
are important for several intrinsic properties, the role of KCNQ2/3 channels in MSN excitability and cocaine-
related molecular and behavioral adaptations has never been studied. In this Proposal, I will test the overarching
hypothesis that KCNQ2/3 channels in the NAc are involved in functional and behavioral plasticity associated with
cocaine-seeking behaviors. Specific Aim 1 of this proposal will use multiple approaches to determine how
KCNQ2/3 channels influence baseline MSN excitability and establish gene-to-function relationships between
KCNQ expression and MSN physiology. Specific Aim 2 will will combine CRISPR/dCas9 tools and cocaine self-
administration to target specific KCNQ2/3-mediated aspects of drug related learning and compulsive drug
seeking. Together, these experiments will define how KCNQ2/3 channels regulate MSN physiology, identify the
relationship between KCNQ subunits and MSN excitability, and determine if KCNQ2/3 channels in the NAc
modulates cocaine-related behavioral plasticity. These studies with reveal previously unknown mechanisms by
which KCNQ2/3 channels contribute to psychostimulant response, and will provide a foundation for future
experiments to explore how KCNQ2/3 channels contribute to motivated behavior.