A Short Video About the Life of Neurons
Rewriting a Receptor’s Role
Synaptic molecule works differently than thought; may mean new therapeutic targets for treating Alzheimer’s diseaseIn a pair of new papers, researchers at the University of California, San Diego School of Medicine and the Royal Netherlands Academy of Arts and Sciences upend a long-held view about the basic functioning of a key receptor molecule involved in signaling between neurons, and describe how a compound linked to Alzheimer’s disease impacts that receptor and weakens synaptic connections between brain cells.
The findings are published in the Feb. 18 early edition of the Proceedings of the National Academy of Sciences.
Long the object of study, the NMDA receptor is located at neuronal synapses – the multitudinous junctions where brain cells trade electrical and chemical messages. In particular, NMDA receptors are ion channels activated by glutamate, a major “excitatory” neurotransmitter associated with cognition, learning and memory.
“NMDA receptors are well known to allow the passage of calcium ions into cells and thereby trigger biochemical signaling,” said principal investigator Roberto Malinow, MD, PhD professor of neurosciences at UC San Diego School of Medicine.
The new research, however, indicates that NMDA receptors can also operate independent of calcium ions. “It turns upside down a view held for decades regarding how NMDA receptors function,” said Malinow, who holds the Shiley-Marcos Endowed Chair in Alzheimer’s Disease Research in Honor of Dr. Leon Thal (a renowned UC San Diego Alzheimer’s disease researcher who died in a single-engine airplane crash in 2007).
Specifically, Malinow and colleagues found that glutamate binding to the NMDA receptor caused conformational changes in the receptor that ultimately resulted in a weakened synapse and impaired brain function.
They also found that beta amyloid – a peptide that comprises the neuron-killing plaques associated with Alzheimer’s disease – causes the NMDA receptor to undergo conformational changes that also lead to the weakening of synapses.
“These new findings overturn commonly held views regarding synapses and potentially identify new targets in the treatment of Alzheimer’s disease,” said Malinow.
People often forget that the lining of your gut is actually a small nervous system in itself, capable of action even in isolation of sympathetic and parasympathetic innervation. It’s a like a small brain for your bowel.
Ulnar Neuropathy
An ulnar neuropathy is damage to the ulnar nerve which traverses medial (pinky side) of each arm. People with ulnar neuropathy often lose sensation or tingling in their pinky and ring fingers (the fourth and fifth digit). On physical exam, one might also find weakness in those fingers. People suffering from an ulnar neruopathy may experience pain in their elbow and may complain of their pinky finger getting caught on their pants pocket due to the fact that they are not able to contract it as strongly. Ulnar neuropathies often arise from compression injuries such as sitting on Tumblr all day with your elbow on your desk…go outside.
Neural Stem Cells Regenerate Axons in Severe Spinal Cord Injury
New relay circuits, formed across sites of complete spinal transaction, result in functional recovery in rats
In a study at the University of California, San Diego and VA San Diego Healthcare, researchers were able to regenerate “an astonishing degree” of axonal growth at the site of severe spinal cord injury in rats. Their research revealed that early stage neurons have the ability to survive and extend axons to form new, functional neuronal relays across an injury site in the adult central nervous system (CNS).
The study also proved that at least some types of adult CNS axons can overcome a normally inhibitory growth environment to grow over long distances. Importantly, stem cells across species exhibit these properties. The work will be published in the journal Cell on September 14.
(For a history of spinal cord repair science and the significance of this latest work, read Ohio State University neuroscientist Phillip Popovich’s review here.)
The UC San Diego-led team embedded neural stem cells in a matrix of fibrin (a protein key to blood-clotting that is already used in human neuron procedures), mixed with growth factors to form a gel. The gel was then applied to the injury site in rats with completely severed spinal cords.
“Using this method, after six weeks, the number of axons emerging from the injury site exceeded by 200-fold what had ever been seen before,” said Mark Tuszynski, MD, PhD, professor in the UC San Diego Department of Neurosciences and director of the UCSD Center for Neural Repair, who headed the study. “The axons also grew 10 times the length of axons in any previous study and, importantly, the regeneration of these axons resulted in significant functional improvement.”
In addition, adult cells above the injury site regenerated into the neural stem cells, establishing a new relay circuit that could be measured electrically. “By stimulating the spinal cord four segments above the injury and recording this electrical stimulation three segments below, we detected new relays across the transaction site,” said Tuszynski.
To confirm that the mechanism underlying recovery was due to formation of new relays, when rats recovered, their spinal cords were re-transected above the implant. The rats lost motor function – confirming formation of new relays across the injury.
The grafting procedure resulted in significant functional improvement: On a 21-point walking scale, without treatment, the rats score was only 1.5; following the stem cell therapy, it rose to 7 – a score reflecting the animals’ ability to move all joints of affected legs.
Results were then replicated using two human stem cell lines, one already in human trials for ALS. “We obtained the exact results using human cells as we had in the rat cells,” said Tuszynski.
The study made use of green fluorescent proteins (GFP), a technique that had never before been used to track neural stem cell growth. “By tagging the cells with GFP, we were able to observe the stem cells grow, become neurons and grow axons, showing us the full ability of these cells to grow and make connections with the host neurons,” said first author Paul Lu, PhD, assistant research scientist at UCSD’s Center for Neural Repair. “This is very exciting, because the technology didn’t exist before.”
Pictured: Artist’s rendering of neurons
Liquefactive necrosis of the brain. Liquefactive necrosis is a type of tissue necrosis (cell death) which occurs primarily in brain tissue and abscesses. This type of necrosis is characterized by the degradation of tissue and replacement by a viscous mass. Here, you can see the liquid quality of the necrosis. While many other tissues will scar, the brain does not have the necessary machinery to generate a fibrotic scar.
Cerebral atrophy.
Death of neurons and other CNS tissues leads to cerebral atrophy. Here you can clearly see the increasing size of the sulci (valleys) as well as narrowing gyri (hills). Cerebral atrophy often occurs as the result of neurodegenerative diseases such as Alzheimer’s. It can also arise following a cerebral infarction.
