journal club stuff Flashcards
overall glycine decarboxylase (GLDC)
effects in mice
causes neural tube defects
cuases features of non-ketotic hyperglycinemia
which mechanism is linked to human neural tube defects (NTDs)
aberrant folate metabolism
effect of Glycine decarboxylase (GLDC) on folate metabolism
provides the carbon units
what do GLDC mutations cause
non-ketonic hyperglycinemia
linked to NTDs
GLDC
glycine decarboxylase
NTD
neural tube defect
mice with reduced GLDC activity
develop (non-ketotic hyperglycinemia) NKH
NTDs
altered folate profiles
administration of formate to mice with reduced GLDC activity
reverses effects of NKH and NTD by providing an alternative source of carbon units and normalising folate profile
mitochondrial folate metabolsim is important in
neural tube development
what are drugs that target GABA signalling used for
anti-anxiety anti-convulsants analgesic anaesthetics muscle relaxants
GABAa receptors
pentometric
ligand-gated ion channels
diverse subunit composition mixture
different subunit compositions of GABAs receptor s
confer different receptor properties
give different physiological effects
different physiological effects of GABAa receptors
drugs have different binding affinities for GABAa receptors
GABAa binding sites
2 orthosteric binding sites
1 allosteric binding/modulatory site
also a possible alternative site
muscimol
selective agonist for GABAa receptor
binds to the orthosteric site
fluni-traz-epam
benzodiazepine
binds to modulatory/allosteric site
allosteric modulator
substance which directly influences the effects of a receptor agonist or inverse agonist at its receptor target
where do allosteric modulators bind
a site distinct from the orthosteric site where a receptor agonist would normally bind
effect of allosteric modulator on structure of receptor
usually induce a conformational change within the protein strucutre
EC10
concentration of an agonist that produces 10% of the maximal possible effect of that agonist
docking binding energy
a measure of how well the ligand binds the receptor binding site
more negative docking binding energy
the better the ligand ‘fits’ the receptor binding site
DCUK-OEt
subunit-selective positive allosteric modulator at the GABAa receptor
where does DCUK-OEt bind to GABAa receptors
appears to act at a site distinct from the benzodiaepine site
example of a monosynaptic pathway
Schaffer Collateral Commissural pathway
Schaffer Collateral Commissural pathway
links CA3 cells to CA1 cells
in hippocampus
monosynaptic pathway
neurotransmitter = glutamate
when action potential arrives via CA3 cells…
voltage gated Ca2+ entry
triggers Glu release at synapses
EPSP induced in CA1 cells
measurements taken in CA1 cells
EPSP recorded with appropriately placed extracellular electrode
how are action potentials evoked in CA3 axons
standard stimulating electrode
how is pre-synaptic Ca2+ measured
using a Ca2+ sensitive fluorescent dye selectively loaded into axons by a local injection
aim of measuring Ca2+ in pre-synaptic neuron
measure Ca2+ transient produced by pre-synaptic action potential
relate this to the post-synaptic response measured electrically
how is the fluorescence from Ca2+ captured
with a photodetector
higher probability of release means that
the electrical response is bigger when Ca2+ entry is promoted
effect of width of action potential
wider AP is better at turning on V.G. Ca2+ channels and leaving them open longer
more Ca2+ entry
how do you manipulate pre-synaptic action potential width
use a drug 4AP which blocks some of the K+ channels involved in AP repolarisatoin
effect of adenosine on Ca2+ entry
acts as an agonist of Gi/o signalling
depresses Ca2+ entry
when was LTP discovered
late 1970s
what is LTP a good model of
how the brain forms and stores new memories
why would a one-trial inhibitory avoidance learning procedure be used
to show that learning can induce changes to synaptic strength
IA learning
inhibitory avoidance learning
effect of IA learning on Glu receptors
induces phosphorylation of specific resideus of GluR1 and GluR2 subunits
suggests learning is inducing changes to post-synaptic receptors
what leads us to believe that subpopulations of synpases are functionally altered following learning
multi-electrode recording reveals that only some recording locations are significantly changed by IA-learning
what do neuro-imaging techniques rely on
the fact that more active areas of the brain require more energy so they need more oxygen and glucose
3 types of neuro-imaging
Arterial spin labelling (ASL)
Blood Oxygen Level Dependent (BOLD)
Magento-encephal-ography (MEG)
features of Arterial spin labelling (ASL)
fMRI technique
doesnt require contrast agent
non-invasive
method of arterial spin labelling (ASL)
modify the magnetization of arterial blood
measure the delivery of
the magnetically tagged blood to target tissues
when is an image acquired in ASL
when the magnetically tagged blood has reached the target tissue
blood oxygen level dependent (BOLD) fMRI
assesses changes in oxygenation in the blood
method of blood oxygen level dependent (BOLD) fMRI
detects differences in magnetic properties of oxyhaemoglobin vs deoxyhaemaglobin
why does magentoencephalography (MEG) work in the brain
synchronised neuronal currents induce weak magnetic fields
what do MEG and EEG signals derive from
the net effect of ionic currents flowing in the dendrites of neurons during synaptic transmission
Maxwell’s equations
any electrical current will induce a magnetic field
how many active neurons are needed to generate a detectable signal
50,000
ASL noise compared to BOLD noise
ASL noise is a lot whiter than BOLD signals
main feature of ASL
does not require contrast agents
changes in perfusion seen in ASL
more localised to parenchyma
changes in perfusion seen in BOLD fMRI
changes are tied to veins and venules
time to collect ASL image
takes longer than BOLD
time to collect BOLD images
can get images in less tahan 500 msec
slices in ASL
fewer at a time with ASL
slices are thicker
challenges with controlling neuroimaging studies in humans
stable baseline measurements
individual differences
specificity of measurements
resolution
potential medical benefits of LSD
reduce anxiety, pain, depression and anorexia nervousa
ethical implication of LSD study
could potentially cause harm
not hypothesis driven
effects variable and not clearly documented
