Role of KCC2 in sympathetic dysfunction after spinal cord injury

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Mariah J Wulf
Organization: DREXEL UNIVERSITY
Fiscal Year: 2024
Award: $48,974
Funding agency: National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY
 Following spinal cord injury (SCI) at or above thoracic level 6 (T6), descending supraspinal control over
the spinal neurons associated with sympathetic function is severed. This, along with plasticity within these
neurons themselves, results in exaggerated sympathetic reflexes known as sympathetic hyperreflexia. This
increase in sympathetic activity following SCI causes severe dysfunction of organs receiving sympathetic input,
such as the spleen and vasculature. This contributes to cardiovascular disease and immune dysfunction, two
leading causes of morbidity and mortality in the SCI population. Therefore, increasing understanding of the
mechanisms underlying this plasticity may identify a possible therapeutic for sympathetic hyperreflexia that would
enormously benefit SCI individuals. SCI-induced reduction of receptor cation-chloride cotransporter type 2
(KCC2) in neuronal membranes disrupts chloride homeostasis to decrease synaptic inhibition and has been
implicated in heightened spinal motor reflexes after SCI. Whether KCC2 contributes to sympathetic hyperreflexia
after SCI is not known. We theorize that SCI results in loss of KCC2 in the membrane of spinal neurons
associated with sympathetic function to contribute to sympathetic hyperreflexia. We also postulate that the loss
of KCC2 in the neuronal membrane results from activation of NF-B, a transcription factor that is downstream of
multiple pro-inflammatory cytokines known to be increased following SCI. This proposal will focus on the
hypothesis that hyperexcitability of spinal, sympathetically-associated neurons after SCI is due to downregulation
of KCC2 expression via increased NF-B activation. The primary goals of this proposal are to: 1) investigate
KCC2 in the development of sympathetic hyperreflexia following SCI and if enhancing KCC2 function mitigates
sympathetic hyperreflexia (Aim 1); 2) determine if SCI-induced KCC2 downregulation occurs via NF-B (Aim 2).

Terms: <Affect><Animals><Atrophic><Atrophy><Attenuated><Autonomic Dysreflexia><Autonomic Hyperreflexia><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><CNS Nervous System><Cardiovascular Diseases><Cations><Cell Communication and Signaling><Cell Signaling><Central Nervous System><Chest><Chlorides><Co-Transporters><Complex><Data><Development><Disease><Disorder><Down-Regulation><Dysfunction><Enhancers><Functional disorder><General Transcription Factor Gene><General Transcription Factors><Goals><Health><Homeostasis><Hyperreflexia><Hypertension><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Individual><Infection><Inflammatory><Injury><Intracellular Communication and Signaling><Knowledge><Lab Findings><Laboratory Finding><Lesion><Life><Mediating><Membrane><Mice><Mice Mammals><Morbidity><Morbidity - disease rate><Motor><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neurons><Organ><Peripheral><Persons><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Play><Population><Predisposition><Receptor Protein><Reflex><Reflex action><Regulation><Reliability of Results><Role><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Spinal><Spinal Autonomic Dysreflexia><Spinal Cord Trauma><Spinal Trauma><Spinal cord injured><Spinal cord injury><Spleen><Spleen Reticuloendothelial System><Susceptibility><System><Testing><Therapeutic><Thorace><Thoracic><Thorax><Time><Transcription Factor Proto-Oncogene><Transcription factor genes><Traumatic Myelopathy><United States><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><attenuate><attenuates><biological signal transduction><cardiovascular disorder><cardiovascular infection><clinical relevance><clinically relevant><conditional knock-out><conditional knockout><cytokine><developmental><flu infection><flu virus infection><functional improvement><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improve function><improved><improved functional outcomes><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><inhibitor><injuries><membrane structure><mortality><mouse model><murine model><neural circuit><neural circuitry><neural inflammation><neurocircuitry><neuroinflammation><neuroinflammatory><neuronal><neuropathologic><neuropathological><neuropathology><pathophysiology><perceptual stimulus><physicochemical phenomena related to the senses><receptor><response><sensory stimulus><social role><symporter><synapse inhibition><synaptic circuit><synaptic circuitry><synaptic inhibition><theories><therapeutic target><transcription factor>