Schizophrenia: glutamate connection

Question 1

what is the glutamate hypothesis

Answer 1

NMDA-R hypoactivity

Question 2

what do NMDAR antagonists cause

Answer 2

PCP and ketamine cause positive, negative and cognitive symptoms

Question 3

what does NMDAR knock down cause

Answer 3

stereotyped behaviours e.g. mice undergoing excessive grooming

Question 4

schizophrenia gene susceptibility

Answer 4

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

Question 5

what does proton spectroscopic imaging show

Answer 5

high glutamate/glutamine signalling levels correlate to high cognitive functioning

no overall difference between normal and schizophrenic patients

hence glutamate levels have no effect

Question 6

NMDA R structure

Answer 6

cation influx
GluN1 subunit - glycine modulatory site
GluN2 subunit - glutamate binding site
Mg2+ blockade

Question 7

what does NMDAR activation require

Answer 7

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

Question 8

evidence of NMDAR hypoactivity

Answer 8

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

Question 9

what does NMDAR hypoactivity explain

Answer 9

hyperactivity of mesolimbic pathway
hypoactivity of mesocortical pathway

Question 10

mesolimbic pathway in normal patients (positive symptoms)

Answer 10

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)

Question 11

mesolimbic pathway in schizophrenia

Answer 11

cortical area degeneration reduces Glu innervation
hypoactivity of NMDAR on gabaergic interneurons prevents GABA release
VTA overactive
disinhibited (higher firing rate)

Question 12

mesocortical pathway in normal patients

Answer 12

mesocortical pathway has no interneurons - direct innervation

descending glutamate pathway stimulates NMDAR and directly tonically activates mesocortical DA pathway - DA released in PFC

Question 13

mesocortical pathway in schizophrenia

Answer 13

NMDAR hypofunction removes stimulation of mesocortical pathway

no DA release in PFC

causes negative and cognitive symptoms

Question 14

therapies to increase NMDAR function

Answer 14

co-agonists (glycine/D-serine) reduces negative and positive symptoms

glycine transport inhibitors (GLYT1) block reuptake into glia to boost glycine co-agonism

Question 15

why is the GMS a target

Answer 15

little innervation is better than excessive innervation (excitiotoxicity)

Question 16

why is there little progress in schizophrenia treatment

Answer 16

lack of mechanistic understanding makes modelling difficult
delusion, hallucinations, disorganised speech cannot be translated into animals
phenotypes examined: hyperlocomotion, avolition (decreased socialisation)

Question 17

different schizophrenia models

Answer 17

12 models based on neurodevelopmental hypothesis - prenatal challenges, maternal malnutrition, isolated rearing

8 drug induced models - methamphetamine, NMDAR antagonists

68 genetic models - NMDAR 1 KO, DISC-1 transgenic, neuregulin KO