Schizophrenia: glutamate connection Flashcards
what is the glutamate hypothesis
NMDA-R hypoactivity
what do NMDAR antagonists cause
PCP and ketamine cause positive, negative and cognitive symptoms
what does NMDAR knock down cause
stereotyped behaviours e.g. mice undergoing excessive grooming
schizophrenia gene susceptibility
dysbindin - regulates vGluT (packages glutamate into vesicles)
DISC-1 - affects transport of synaptic vesicles into presynaptic glutamate terminals
DAOA - degrades D-serine
dysbindin, DISC-1, neuregulin - alter NMDAR trafficking and tethering in post synaptic membrane
what does proton spectroscopic imaging show
high glutamate/glutamine signalling levels correlate to high cognitive functioning
no overall difference between normal and schizophrenic patients
hence glutamate levels have no effect
NMDA R structure
cation influx
GluN1 subunit - glycine modulatory site
GluN2 subunit - glutamate binding site
Mg2+ blockade
what does NMDAR activation require
main agonist (glutamate)
post-synaptic depolarisation which relieves Mg+ block
co-agonists glycine/D-serine which are present in the extracellular space - not saturated in vivo
evidence of NMDAR hypoactivity
reduced serine racemase (enzyme) in PM brains (converts L-serine to D-serine)
reduced D-serine in CSF and plasma (not in all studies)
reduced plasma glycine correlates with negative symptoms
decreased expression of GluN1 mRNA and protein (reduced transcription) in PFC and hippocampus
what does NMDAR hypoactivity explain
hyperactivity of mesolimbic pathway
hypoactivity of mesocortical pathway
mesolimbic pathway in normal patients (positive symptoms)
descending glutamatergic pathway is tonically active
glutamate binds to NMDAR on GABAergic interneurons
relays to VTA
N.accumbens
flood of inhibitory GABA switches off mesolimbic pathway (tonically inhibited - low tonic firing)
mesolimbic pathway in schizophrenia
cortical area degeneration reduces Glu innervation
hypoactivity of NMDAR on gabaergic interneurons prevents GABA release
VTA overactive
disinhibited (higher firing rate)
mesocortical pathway in normal patients
mesocortical pathway has no interneurons - direct innervation
descending glutamate pathway stimulates NMDAR and directly tonically activates mesocortical DA pathway - DA released in PFC
mesocortical pathway in schizophrenia
NMDAR hypofunction removes stimulation of mesocortical pathway
no DA release in PFC
causes negative and cognitive symptoms
therapies to increase NMDAR function
co-agonists (glycine/D-serine) reduces negative and positive symptoms
glycine transport inhibitors (GLYT1) block reuptake into glia to boost glycine co-agonism
why is the GMS a target
little innervation is better than excessive innervation (excitiotoxicity)
