Power, J. M. | bioRxiv Science

bioRxiv2018

Conditional upregulation of KCC2 selectively enhances neuronal inhibition during seizures

Abstract/SummaryEfficacious neuronal inhibition is sustained by the neuronal K+Cl- co-transporter KCC2, and loss of KCC2 function through injury or mutation is associated with altered GABAergic signalling and neuronal seizures. Here we report a transgenic mouse with conditional KCC2 overexpression that results in increased membrane transport function. Increased KCC2 has little impact on behavioural and in vitro assays of neuronal excitability and GABAA receptor responses under resting conditions. In contrast, increased KCC2 imparts resistance to seizure-like neuronal activity in hippocampal slices and prevents the progression of mice into behavioural status epilepticus following multiple kainic acid doses. Our results demonstrate a transgenic mouse to facilitate investigations into the role of KCC2 in brain function, and provide a proof of principle that targeting KCC2 may be an effective way to selectively enhance neuronal inhibition to mitigate against diseases that involve an imbalance between excitation and inhibition.

neuroscience↗

bioRxiv2017

Basolateral amygdala glutamatergic neurons maintain aversive emotional salience

Basolateral amygdala (BLA) glutamatergic neurons serve a well-accepted role in fear conditioning and fear extinction. However, the specific learning processes related to their activity at different times during learning remain poorly understood. We addressed this using behavioral tasks isolating distinct aspects of fear learning in rats. We show that brief optogenetic inhibition of BLA glutamatergic neurons around moments of aversive reinforcement or non-reinforcement causes reductions in the salience of conditioned stimuli, rendering these stimuli less able to be learned about and less able to control fear or safety behaviours. This salience reduction was stimulus-specific, long-lasting, and specific to aversive emotional states - precisely the goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition. They show that a primary function of BLA glutamatergic neurons is to maintain the salience of conditioned stimuli. This is a necessary precursor for these stimuli to gain and maintain control over fear and safety behavior.\n\nSignificance statementThe amygdala is essential for learning to fear and learning to reduce fear. However, the specific roles served by activity of different amygdala neurons at different times during learning is poorly understood. We used behavioral tasks isolating distinct aspects of learning in rats to show that brief optogenetic inhibition of BLA glutamatergic neurons around moments of reinforcement or non-reinforcement disrupts maintenance of conditioned stimulus (CS) salience. This causes a stimulus-specific, long-lasting, and aversive emotion specific deficit in the ability of the CS to be learned about or control fear responses. These consequences are the precisely goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition.

neuroscience↗