Module II - Psychosis Flashcards
The pedunculopontine tegmentum (PPTg) and salience:
When an animal is exposed to a behaviorally salient stimulus, the PPTg elicits a burst of action potentials in the dopamine neurons. However, this bursting only occurs in the portion of the dopamine neuron population that is firing sponta- neously. This proportion is regulated by the ventral subiculum. Therefore, the ventral subiculum provides the gain, or the amplification factor, for the behaviorally salient stimulus.
DA neuron firing depends on the PPTg:
a salient stimulus will activate burst firing in spontaneously firing DA neurons via activation of the PPTg. However, the number of DA neurons that are driven to burst fire will depend on the population activity. Therefore, the more DA neurons firing, the larger the amplitude of the phasic response
The ventral subiculum in rodents is the homolog of…
…the anterior hippocampus in humans
What is the ventral subiculum involved in?
- moving from the dorsal hippocampus (place cells) ventrally, it seems that place information becomes more integrated with limbic input.
- the ventral subiculum is involved in context-dependent fear conditioning and other context-related processes
(the amplitude of the stimulus-driven phasic response of the DA system should be a function of the behavioral context of the event)
Catechol-O-methyl-transferase enzyme:
- responsible for the metabolism of DA in the PFC
- polymorphisms linked to increased risk of psychosis
Population activity of DA neurons
Approximately half of the dopamine neurons are firing in the control rat; a parameter known as population activity. Since dopamine neurons are driven by a pacemaker conductance, the nonfiring state must be maintained by an active inhibitory input.
How does hippocampal activation lead to DA firing?
- The ventral hippocampus projects to the nAcc
- the nAcc inhibits the ventral pallidum
- the ventral pallidum is inhibited and thus releases DA neurons from inhibition
Interplay between the ventral hippocampus and the PPTg
The ventral hippocampus is positioned to modulate the amplitude of the phasic dopamine signal; i.e., the pedunculopontine tegmentum provides the behaviorally salient phasic drive, but the ventral hippocampus determines the amplitude of the phasic dopamine response.
What is the source of hippocampal hyperactivity in SCZ patients?
…the limbic hippocampal region has shown to exhibit a significant reduction in staining for a particular class of GABAergic interneurons; i.e., those containing the marker parvalbumin
the impact of stressful stimuli on the amygdala is attenuated via…
…activation of the m PFC
Effects of the 2 classes of DA receptors:
D1 - stimulates cAMP - PKA
- ERK - MAPK pathway
D2:
- inhibits cAMP
- modulates Ca++ signalling
- non-canonical (G-protein-independent) pathway: inhibits AKT1, stimulates GSK3beta
D2-AKT-GSK3b signalling
D2R activation can be mediated through a β-arrestin 2 (βarr2)-dependent signaling complex composed of βarr2/protein kinase B (Akt)/protein phosphatase 2A (PP2A), which leads to the activation of glycogen synthase kinase 3 β (GSK3β)
Different timeframes of the two D2R cascades in response to drugs:
- G-protein-mediated - peak at 15min, end at 30
- b-arrestin 2 mediated - peak around 80min, end at 120
Akt1 expression in SCZ
- Akt 1 expression is decreased in SCZ in hippocampus and especially in the PFC, whereas active GSK3b levels are higher (since it is inactivated by Akt1), resulting in a hyperdopaminergic response
Effects of stress on Akt1:
- Akt1 activity is decreased in response to stress in the VTA leading to:
- reduced tonic GABAergic inhibition
- hyper DA firing
