Excitatory synaptogenesis causes autonomic dysreflexia after spinal cord injury
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Date
2017-03
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Abstract
Spinal cord injury (SCI) causes devastating damage to an individual leading to life long consequences. The most commonly considered and researched consequences of SCI are deficits in motor and sensory systems below the level of injury. However, more recent work has begun to elucidate systemic effects of SCI, such as chronic deficits in the autonomic nervous system and immune function. An example of a deficit of the autonomic nervous system is autonomic dysreflexia (AD), a potentially fatal complication of high-level SCI marked by the sudden onset of an excessively high blood pressure. Concurrent with the presentation of these deficits, the intraspinal circuitry above and below the level of injury undergoes a period of structural and molecular plasticity. Recent research from our lab has shown a direct relationship between the changing autonomic circuitry of the spinal cord in response to injury, the onset of AD, and immune suppression. Significant work has been done to characterize and manipulate plasticity in the motor and sensory systems, but comparatively less is known about plasticity in the autonomic nervous system. In this study, we will fully characterize the time-dependent changes that occur in autonomic circuitry following SCI and the functional implications of this plasticity.
Additionally, we will investigate the contribution autonomic plasticity is having on the development of autonomic dysreflexia (AD), a potentially fatal complication of spinal cord injuries (SCI) occurring at or above the fifth thoracic vertebral level. The hallmark symptom of AD is unchecked activation of the spinal autonomic (sympathetic) reflexes. The cardiovascular dysfunction that occurs during episodes of AD is caused, in part, by unregulated activation of sympathetic reflexes below the level of injury. This can lead to various complications ranging from sweating and headaches to cerebral hemorrhage and death. Our previous work has also implicated immune suppression with AD. Using in vivo recording of blood pressure and heart rate, we have shown that AD develops spontaneously in mice with high level SCI -- with the number of dysreflexic episodes increasing as a function of time post-injury. The mechanisms responsible for the onset and progression of AD are not well defined, but since supraspinal brain connections are mostly lost after high-level SCI, maladaptive plasticity within “presympathetic” neurons (neurons synapsing on the sympathetic preganglionic neurons of the autonomic nervous system), especially those originating from the brainstem and segmental interneurons, is expected. We hypothesize that spinal cord injury causes aberrant plasticity in autonomic circuitry leading to autonomic dysfunction. Inhibiting this aberrant spinal autonomic circuitry will decrease the frequency and severity of AD and related complications, including immune suppression.
To test this hypothesis, we quantified the overall number of synapses, defined by the colocalization of pre- and post-synaptic markers, in the region of the spinal cord where most autonomic neurons reside. Our data reveal a progressive increase in excitatory synapses over time. The timing of this excitatory synapse formation coincides with an increase in number and severity of dysreflexic episodes, suggesting a direct link between post-SCI synaptogenesis and AD. Although additional data are needed, the current study suggests post-injury synaptogenesis is contributing to the development of AD. To definitively establish a direct relationship between this circuitry and AD development, we are investigating novel ways to modify or silence the newly developed circuitry of the injured spinal cord. We are utilizing Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). DREADDs are specially designed receptors that can be targeted to a specific subtype of cells. These G-protein coupled receptors can be designed to be either excitatory or inhibitory, and to target excitatory or inhibitory neurons. For this study, we are utilizing inhibitory DREADD receptors targeting neurons we have already shown to be a part of the newly developed excitatory circuitry in the IML of the injured spinal cord. Studies have already shown that the silencing of this autonomic circuitry can ameliorate certain sequelae of AD, such as immune suppression. And, although preliminary, we have evidence to suggest that chemogenetics are preserving immune function by directly decreasing the frequency and severity of AD. AD and related bladder, bowel, and sexual function are among the top priorities of SCI patients. Understanding the mechanisms responsible for AD, and developing new treatments to prevent it, could also have implications for other disabling secondary disorders of SCI with plasticity-related causes, like chronic pain and muscle spasticity.
Description
Poster Division: Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
spinal cord injury, autonomic dysreflexia, neuroplasticity