Synaptic inhibition plays a crucial role in regulating neuronal excitability, which is the foundation of nervous system function. This inhibition is largely mediated by the neurotransmitters GABA and glycine that activate Cl--permeable ion channels, which means that the strength of inhibition depends on the Cl- gradient across the membrane. In neurons, the Cl- gradient is primarily determined by two secondarily-active cation-chloride cotransporters (CCCs), NKCC1 and KCC2. CCC-mediated regulation of the neuronal Cl- gradient is critical for healthy brain function, as dysregulation of CCCs has emerged as a key mechanism underlying neurological disorders including epilepsy, neuropathic pain, and autism spectrum disorder. This Review begins with an overview of neuronal chloride transporters before explaining the dependent relationship between these CCCs, Cl- regulation, and inhibitory synaptic transmission. We then discuss the evidence for how CCCs can be regulated, including by activity and their protein interactions, which underlie inhibitory synaptic plasticity. For readers who may be interested in conducting experiments on CCCs and neuronal excitability, we have included a section on techniques for estimating and recording intracellular Cl-, including their advantages and limitations. While the focus of this Review is on neurons, we also examine how Cl- is regulated in glial cells, which in turn regulate neuronal excitability through the tight relationship between this non-neuronal cell type and synapses. Lastly, we discuss the relatively extensive and growing literature on how CCC-mediated neuronal excitability contributes to neurological disorders.

ABSTRACT:Background:Involving stakeholders has been acknowledged as a way to improve quality and relevance in health research. The mechanisms that support effective research engagement with stakeholders have not been studied in the area of concussion. Concussion is a large public health concern worldwide with billions of dollars spent on health care services and research with improvements in care and service delivery not moving forward as quickly as desired. Enabling effective stakeholder engagement could improve concussion research and care.Objective:The aim of the study was to identify potential benefits, challenges, and motivators to engaging in research by gathering the perspectives of adults with lived experience of concussion.Methods:A thematic analysis of qualitative responses collected from a convenience sample attending a provincial brain injury conference (n = 60) was undertaken using open coding followed by axial coding.Results:Four themes regarding benefits to engagement emerged: first-hand account, meaningful recovery, research relevance, and better understanding of gaps. Three forces inhibited engagement: environmental barriers, injury-related constraints, and personal deterrents. Four enablers supported engagement: focus on positive impact, build connections, create a supportive environment, and provide financial assistance.Conclusions:Understanding stakeholder’s perspectives on research engagement is an important issue that may serve to improve research quality. There may be unique nuances at play with injury-specific stakeholders that require researchers to consider a balance between reducing inhibitors while supporting enablers. These findings are preliminary and limited. Nevertheless, they provide needed insight and guidance for ongoing investigation regarding improvement of stakeholder engagement in concussion research.