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William F Colmers PhD

MEMBER SINCE: Nov 30, 2005
LAST UPDATED: Apr 26, 2017

PROFILE: Professor of Pharmacology and AHFMR Medical Scientist, Department of Pharmacology, University of Alberta, Edmonton, Alberta

My laboratory uses electrophysiological methods and digital imaging in brain slices in vitro to study the neuroscience of obesity, by examining the actions of endogenous neurotransmitters in the central nervous system. The goal of my laboratory is twofold: to understand the biological role which the neuromodulator, Neuropeptide Y (NPY) plays in different regions of the mammalian brain, and to understand mechanisms by which receptors can regulate the release of transmitter from presynaptic terminals. Relevant diseases include epilepsy and obesity.

Neuropeptide Y (NPY) is a member of a family of peptides which include pancreatic polypeptide (PP-the first one discovered), Peptide YY (PYY) and structurally-related peptides. NPY occurs in most regions of the mammalian brain. In brainstem nuclei, NPY is most commonly found in neurons that also express catecholamines, predominantly norepinephrine, and which project to different regions of the brain. In the hippocampus and cortex, NPY is most often colocalized with GABA and/or somatostatin in neurons that appear to be predominantly local circuit (interneurons).

Receptors: At the present time, there are 6 known receptors for NPY, five of which have been cloned and expressed. For historical reasons, they are numbered Y1, Y2, Y3 Y4/PP1, Y5 and Y6, and can be told apart by responses to different agonist fragments and recently-developed antagonists. In the rat hippocampus, most of the receptors appear to be of the Y2 subtype, although there is a reasonable concentration of Y1 receptors in the dentate gyrus and some Y5 receptors in the subiculum. In the human brain, binding for Y2 receptors dominates, but message and binding is also present for Y1 and Y5. Y5 has a broad affinity spectrum, with the only selective agonist at present being D-Trp32NPY and D-Trp34NPY. Y5 has been implicated in the stunning increases in food intake seen with injection of NPY into the hypothalamus.

Hippocampus: In transverse slices of rat hippocampus, NPY causes a marked and selective reduction in excitatory synaptic transmission between principal neurons (pyramidal cells and dentate granule cells), while not affecting the synaptic release of GABA, the major inhibitory amino acid transmitter. NPY acts via a Y2 receptor in rat hippocampus, and it appears to inhibit only the Ca2+-dependent release of glutamate by inhibiting presynaptic Ca2+influx through N- P/Q and R- type Ca2+ channels.

In the dentate gyrus, we have shown that NPY inhibits N-type Ca2+currents in dentate granule cells, which could be very important in controlling the release of the peptide dynorphin from the soma and dendrites, in addition to possibly affecting dendritic properties. Dynorphin inhibits hippocampal interneurons, permitting excitation to spread; NPY is poised to regulate the release of dynorphin, and thus regulate the level of disinhibition in the dentate gyrus.

Epilepsy: Because of the remarkably selective inhibition of glutamate release, we have hypothesized that NPY receptors may prevent inappropriate excitation. In several in vitro slice models of epilepsy, NPY strongly inhibits epileptic activity. In recent experiments with human brain tissue removed for medically-intractable epilepsy, NPY has been shown to be very effective at inhibiting synaptic excitation of pyramidal cells. This is an area of intense current activity in my laboratory, funded by CIHR and the Human Frontiers Science Program.

Hypothalamus: As mentioned above, NPY causes a remarkable increase in food intake, even in full-satiated animals, when injected into some areas of the hypothalamus. We are examining the mechanism by which NPY causes this increase in the paraventricular nucleus of the hypothalamus. Neurons there receive excitatory and inhibitory synaptic inputs. NPY application reduces the release of GABA, which would result in the net excitation of the cells.

Future Work: Future work includes further characterization of the NPY responses in human brain and in other models of epilepsy, a study of the action of NPY in the cortex of knockout mice, rats and humans, further studies of the hypothalmic machinery that regulates appetite, including several other peptides, and studies into the mechanisms and consequences of presynaptic inhibition in the mammalian CNS.

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Inst./Company University of Alberta
Dept. Department of Pharmacology
Position Professor and AHFMR Medical Scientist
Province AB
Country Canada
Category Post-Doc
Faculty Yes
Member Id# 209

William F Colmers


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