Khris Griffis - Academia.edu (original) (raw)

Papers by Khris Griffis

The Journal of Neuroscience, Jun 8, 2016

Multiple neural and peripheral cell types rapidly respond to tissue damage after spinal cord inju... more Multiple neural and peripheral cell types rapidly respond to tissue damage after spinal cord injury to form a structurally and chemically inhibitory scar that limits axon regeneration. Astrocytes form an astroglial scar and produce chondroitin sulfate proteoglycans (CSPGs), activate microglia, and recruit blood-derived immune cells to the lesion for debris removal. One beneficial therapy, olfactory ensheathing cell (OEC) transplantation, results in functional improvements and promotes axon regeneration after spinal cord injury. The lack of an OEC-specific marker, however, has limited the investigation of mechanisms underlying their proregenerative effects. We compared the effects of enhanced green fluorescent protein-labeled fibroblast (FB) and OEC transplants acutely after a complete low-thoracic spinal cord transection in adult rats. We assessed the preservation of neurons and serotonergic axons, the levels of inhibitory CSPGs and myelin debris, and the extent of immune cell activation between 1 and 8 weeks postinjury. Our findings indicate that OECs survive longer than FBs post-transplantation, preserve axons and neurons, and reduce inhibitory molecules in the lesion core. Additionally, we show that OECs limit immune-cell activation and infiltration, whereas FBs alter astroglial scar formation and increase immune-cell infiltration and concomitant secondary tissue damage. Administration of cyclosporine-A to enhance graft survival demonstrated that immune suppression can augment OEC contact-mediated protection of axons and neurons during the first 2 weeks postinjury. Collectively, these data suggest that OECs have neuroprotective and immunomodulatory mechanisms that create a supportive environment for neuronal survival and axon regeneration after spinal cord injury.

International Journal of Molecular Sciences

Mammalian UNC119 is a ciliary trafficking chaperone highly expressed in the inner segment of reti... more Mammalian UNC119 is a ciliary trafficking chaperone highly expressed in the inner segment of retinal photoreceptors. Previous research has shown that UNC119 can bind to transducin, the synaptic ribbon protein RIBEYE, and the calcium-binding protein CaBP4, suggesting that UNC119 may have a role in synaptic transmission. We made patch-clamp recordings from retinal slices in mice with the UNC119 gene deleted and showed that removal of even one gene of UNC119 has no effect on the rod outer segment photocurrent, but acted on bipolar cells much like background light: it depolarized membrane potential, decreased sensitivity, accelerated response decay, and decreased the Hill coefficient of the response–intensity relationship. Similar effects were seen on rod bipolar-cell current and voltage responses, and after exposure to bright light to translocate transducin into the rod inner segment. These findings indicate that UNC119 deletion reduces the steady-state glutamate release rate at rod sy...

Calcium Oscillations in Human Pulmonary Artery Smooth Muscle Cells: Developing a Hierarchical Clustering Method for Analysis and the Effects of IL‐1b

The FASEB Journal, 2018

The Journal of Physiology, 2020

Key points Most vertebrate eyes have rods for dim‐light vision and cones for brighter light and h... more Key points Most vertebrate eyes have rods for dim‐light vision and cones for brighter light and higher temporal sensitivity. Rods evolved from cone‐like precursors through expression of different transduction genes or the same genes at different expression levels, but we do not know which molecular differences were most important. We approached this problem by analysing rod and cone responses with the same model but with different values for model parameters. We showed that, in addition to outer‐segment volume, the most important differences between rods and cones are: (1) decreased transduction gain, reflecting smaller amplification in the G‐protein cascade; (2) a faster rate of turnover of the second messenger cGMP in darkness; and (3) an accelerated rate of decay of the effector enzyme phosphodiesterase and perhaps also of activated visual pigment. We believe our analysis has identified the principal alterations during evolution responsible for the duplex retina. Most vertebrates...

Experimental Neurology, 2018

Olfactory ensheathing cells (OECs) are unique glia that support axon outgrowth in the olfactory s... more Olfactory ensheathing cells (OECs) are unique glia that support axon outgrowth in the olfactory system, and when used as cellular therapy after spinal cord injury, improve recovery and axon regeneration. Here we assessed the effects of combining OEC transplantation with another promising therapy, epidural electrical stimulation during a rehabilitative motor task. Sprague-Dawley rats received a mid-thoracic transection and transplantation of OECs or fibroblasts (FBs) followed by lumbar stimulation while climbing an inclined grid. We injected pseudorabies virus (PRV) into hindlimb muscles 7 months post-injury to assess connectivity across the transection. Analyses showed that the number of serotonergic (5-HT) axons that crossed the rostral scar border and the area of neurofilament-positive axons in the injury site were both greater in OEC-than FBtreated rats. We detected PRV-labeled cells rostral to the transection and remarkable evidence of 5-HT and PRV axons crossing the injury site in 1 OEC-and 1 FB-treated rat. The axons that crossed suggested either axon regeneration (OEC) or small areas of probable tissue sparing (FB). Most PRV-labeled thoracic neurons were detected in laminae VII or X, and ~25% expressed Chx10, a marker for V2a interneurons. These findings suggest potential regeneration or sparing of circuits that connect thoracic interneurons to lumbar somatic motor neurons. Despite evidence of axonal connectivity, no behavioral changes were detected in this small-scale study. Together these data suggest that when supplemented with epidural stimulation and climbing, OEC transplantation can increase axonal growth across the injury site and may promote recovery of propriospinal circuitry.

Olfactory ensheathing cell transplantation as a strategy for spinal cord repair—what can it achieve?

Nature Clinical Practice Neurology, 2007

Restoring function to the injured spinal cord represents one of the most formidable challenges in... more Restoring function to the injured spinal cord represents one of the most formidable challenges in regenerative medicine. Glial cell transplantation is widely considered to be one of the most promising therapeutic strategies, and several differentiated glial cell types-in particular, Schwann cells and olfactory ensheathing cells (OECs)-have been proposed as transplant candidates. In this Review, we analyze evidence from animal studies for improved functional recovery following transplantation of OECs into spinal cord injuries, and examine the mechanisms by which repair might be achieved. Data obtained using various injury models support the view that OEC transplants can promote functional recovery, but accumulating anatomical evidence indicates that although axons regenerate within a transplant, they do not cross the lesion or reconnect with neurons on the opposite side to any significant extent. Consequently, it is possible that neuroprotection and promotion of sprouting from intact fibers are the main mechanisms that contribute to functional recovery. We conclude that for the foreseeable future the clinical benefits of OEC transplants alone are likely to be modest. The future potential of cell transplantation strategies will probably depend on the success with which the transplants can be combined with other, synergistic, therapies to achieve significant regeneration of axons and re-establish functionally useful connections across a spinal cord injury.

Light Adaptation of Retinal Rod Bipolar Cells

The Journal of Neuroscience

The sensitivity of retinal cells is altered in background light to optimize the detection of cont... more The sensitivity of retinal cells is altered in background light to optimize the detection of contrast. For scotopic (rod) vision, substantial adaptation occurs in the first two cells, the rods and rod bipolar cells (RBCs), through sensitivity adjustments in rods and postsynaptic modulation of the transduction cascade in RBCs. To study the mechanisms mediating these components of adaptation, we made whole-cell, voltage-clamp recordings from retinal slices of mice from both sexes. Adaptation was assessed by fitting the Hill equation to response-intensity relationships with the parameters of half-maximal response (I1/2), Hill coefficient (n), and maximum response amplitude (Rmax). We show that rod sensitivity decreases in backgrounds according to the Weber–Fechner relation with anI1/2of ∼50 R* s−1. The sensitivity of RBCs follows a near-identical function, indicating that changes in RBC sensitivity in backgrounds bright enough to adapt the rods are mostly derived from the rods themselv...