The Glutamate Hypothesis Flashcards
Why is this better than dopamine hypothesis?
It explains the positive and negative symptoms and understand the way that dopamine is unbalanced in both systems
What is the glutamate system?
The main excitatory neurotransmitter - most prevalent one. 50% of neurons in the brain use glutamate as their NT. Glutamate is balanced with GABA in the brain. Both neurotransmitters influence other chemical and brain areas. Evidence implicates NMDA receptors in schziophrenia
What does tetrameter mean?
The NMDA receptor has many subunits - NR1 and NR2
What can change the NMDA receptor?
A mutation in a subunit of the receptor - makes a difference which subunit we have
What have animal models shown?
GRIN1 gene codes for NR1 NMDA receptor subunit - NR1 knock-out mice exhibit signs of schizophrenia
GRIN2A - gene that codes for NRA2 NMDA receptor subunit in frontal cortex - mice lacking this behave in a similar way to patients
What are NMDA receptors involved in?
Developmental processes: neural pathways neural migration neural survival plasticity pruninng apoptosis mutation can cause problems when developing schizophrenia
What is the hypothesis?
Schizophrenia is due to NMDA receptor hypofunction which can explain:
why there are treatment resistant negative symptoms
why the disease occurs in adulthood
why it is associated with structural changes and cognitive deficits
Is there evidence to support?
The drugs PCP and ketamine can cause positive, negative and cognitive symptoms - they are both NMDA receptor antagonists
Glutamate agonists seem to improve both positive and negative symptoms of schizophrenia
What are the negative and cognitive symptoms produced by ketamine and PCP caused by?
Decrease in the metabolic activity of the frontal lobes
Jentsch et al - PCP administered to monkeys
PCP given to monkeys twice a day for two weeks
a week later - tested the animals on a task that involved reaching around a barrier for a piece of food, this is performed poorly by monkeys with lesions in pre fontal cortex. Control monkeys were okay, but those treated with PCP showed a deficit - shows it could be dysfunction of patients frontal lobes and the NMDA receptor
How does the glutamate hypothesis explain the positive symptoms?
Normal conditions:
glutamate synapses on a GABA neuron, stimulating it, causing inhibition of the glutamate projection. Results in normal inhibition and excitation - so normal dopamine and glutamate
Patient:
the NMDA receptor in the GABAergic neuron isn’t working. Glutamate synapses on GABA, trying to stimulate it but NMDA isn’t functioning, so GABA isn’t able to inhibit the glutamate projected to the mesolimbic system. This means that the glutamate going to the VTA hasn’t been inhibited, so the dopamine neuron is overstimulated, causing overproduction of dopamine in the mesolimbic system - causing the positive symptoms
How does the glutamate hypothesis explain the negative and cognitive symptoms?
Normal conditions:
Glutamate projects to GABa, but in the mesocortiyal pathway, there is another GABA interneuron in the VTA. Glutamate is inhibited normally by GABA, inhibiting a normal level of dopamine
Patient:
Glutamate is synapsing on the GABA neuron which has a dysfunctional NMDA receptor in the frontal cortex. Glutamate released but GABA doesn’t respond, cant inhibit it, so there is more glutamate coming down to VTA. This glutamate will stimulate the GABA interneuron - overexcite it because the signal is powerful - so it will inhibit the dopamine signal trying to reach the cortex. Gives rise to the hyperfrontality and the negative and cognitive symptoms
What is good about the theory?
More comprehensive and can explain positive, negative and cognitive symptoms
Accounts for the lack of effectiveness of DA antagonists in treating schizophrenia
Hypofunctioning NMDA receptors can account for the excessive DA release in the mesolimbic DA system as well as the reduced release of DA in the prefrontal cortex
What causes the positive symptoms and the negative and cognitive symptoms?
Positive - overactivity of dopamine in the mesolimbic system
Negative and Cognitive - hypofrontality in the prefrontal cortex
