Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell

• Published in: Neuropharmacology 2017-05, Vol.117, p.49-60
• Main Authors: Crofton, Elizabeth J., Nenov, Miroslav N., Zhang, Yafang, Scala, Federico, Page, Sean A., McCue, David L., Li, Dingge, Hommel, Jonathan D., Laezza, Fernanda, Green, Thomas A.
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Anxiety - genetics; Behavior, Addictive - genetics; Behavior, Animal - physiology; Cocaine; Cocaine - pharmacology; Depression; Depression - genetics; Drug addiction; Gene Knockdown Techniques; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - physiology; Interneurons - physiology; Male; Nucleus accumbens; Nucleus Accumbens - physiology; Rats; Self Administration; Tonically active neurons
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2017.01.020

Psychiatric disorders such as anxiety, depression and addiction are often comorbid brain pathologies thought to share common mechanistic biology. As part of the cortico-limbic circuit, the nucleus accumbens shell (NAcSh) plays a fundamental role in integrating information in the circuit, such that modulation of NAcSh circuitry alters anxiety, depression, and addiction-related behaviors. Intracellular kinase cascades in the NAcSh have proven important mediators of behavior. To investigate glycogen-synthase kinase 3 (GSK3) beta signaling in the NAcSh in vivo we knocked down GSK3beta expression with a novel adeno-associated viral vector (AAV2) and assessed changes in anxiety- and depression-like behavior and cocaine self-administration in GSK3beta knockdown rats. GSK3beta knockdown reduced anxiety-like behavior while increasing depression-like behavior and cocaine self-administration. Correlative electrophysiological recordings in acute brain slices were used to assess the effect of AAV-shGSK3beta on spontaneous firing and intrinsic excitability of tonically active interneurons (TANs), cells required for input and output signal integration in the NAcSh and for processing reward-related behaviors. Loose-patch recordings showed that TANs transduced by AAV-shGSK3beta exhibited reduction in tonic firing and increased spike half width. When assessed by whole-cell patch clamp recordings these changes were mirrored by reduction in action potential firing and accompanied by decreased hyperpolarization-induced depolarizing sag potentials, increased action potential current threshold, and decreased maximum rise time. These results suggest that silencing of GSK3beta in the NAcSh increases depression- and addiction-related behavior, possibly by decreasing intrinsic excitability of TANs. However, this study does not rule out contributions from other neuronal sub-types. •Specific knockdown of GSK3 beta in the NAc shell induces an anxiolytic-like effect.•Knockdown of GSK3 beta in the NAcSh induces depression-like behavior.•Viral-mediated knockdown of GSK3 beta increases cocaine self-administration.•Knockdown also reduces spontaneous firing and alters intrinsic excitability of TANs.