Abstract
Pathological impairments in the regulation of affect (i.e., emotion) and flexible decision-making are commonly observed across numerous neuropsychiatric disorders and are thought to reflect dysfunction of cortical and subcortical circuits that arise in part from imbalances in excitation and inhibition within these structures. Disruptions in GABA transmission, in particular, that from parvalbumin-expressing interneurons (PVI), has been highlighted as a likely mechanism by which this imbalance arises, as they regulate excitation and synchronization of principle output neurons. G protein-gated inwardly rectifying potassium ion (GIRK/Kir3) channels are known to modulate excitability and output of pyramidal neurons in areas like the medial prefrontal cortex and hippocampus; however, the role GIRK plays in PVI excitability and behavior is unknown. Male and female mice lacking GIRK1 in PVI (Girk1flox/flox:PVcre) and expressing td-tomato in PVI (Girk1flox/flox:PVCre:PVtdtom) exhibited increased open arm time in the elevated plus-maze, while males showed an increase in immobile episodes during the forced swim test (FST). Loss of GIRK1 did not alter motivated behavior for an appetitive reward or impair overall performance in an operant-based attention set-shifting model of cognitive flexibility; however it did alter types of errors committed during the visual cue test. Unexpectedly, baseline sex differences were also identified in these tasks, with females exhibiting overall poorer performance compared to males and distinct types of errors, highlighting potential differences in task-related problem-solving. Interestingly, reductions in PVI GIRK signaling did not correspond to changes in membrane excitability but did increase action potential (AP) firing at higher current injections in PVI of males, but not females. This is the first investigation on the role that PVI GIRK-signaling has on membrane excitability, AP firing, and their role on affect and cognition together increasing the understanding of PVI cellular mechanisms and function.
Highlights
Cognitive flexibility is the ability to adapt behavior in response to changing environmental contingencies and is a critical component of everyday life
As GIRK channels are known to be present in parvalbumin-expressing interneurons (PVI), and alteration of PV-dependent GABA neuron activity is known to regulate affect and cognitive control (Sohal et al, 2009; Rossi et al, 2012; Sparta et al, 2014; Murray et al, 2015; Kim et al, 2016b; Page et al, 2019), we aimed to determine whether GIRK1-dependent signaling in PVI is necessary for normal affect, motivation, and cognitive control
The current study evaluated the impact of selectively ablating GIRK channels expressing the GIRK1 subunit in PVI on affect and cognitive flexibility
Summary
Cognitive flexibility is the ability to adapt behavior in response to changing environmental contingencies and is a critical component of everyday life. Impairments in flexibility increase susceptibility to negative life events (e.g., stress), reduce emotional control, and promote the development of maladaptive behaviors that can disrupt the capacity of individuals to engage in their lives effectively (Lange et al, 2017; Waltz, 2017; Gabrys et al, 2018) Neuropsychiatric disorders such as major depressive disorder (MDD), obsessive-compulsive disorder (OCD), autism, and schizophrenia share common symptomology including cognitive inflexibility, reduced inhibitory control, and impaired working memory (Marazziti et al, 2010; Moghaddam and Javitt, 2012; Diamond, 2013; Etkin et al, 2013; Remijnse et al, 2013; Dajani and Uddin, 2015); what contributes to these impairments is not well understood. Loss of parvalbumin in rodents promotes autism- (Wöhr et al, 2015) and depression-like symptoms (Fogaça and Duman, 2019), together suggesting a role for parvalbumin and PVI in related neuropsychiatric disorder symptomatology
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