Role of glutaminergic system

Question 1

Chronic intraventricular infusion of d,l-AP5 (blocks NMDA receptors). Study in rats.

1) Selective impairment of place learning in rats on the Morris Water Maze Task.
i. e. in transfer test (after multiple training trials with platform in same place) D,L-AP5 group showed little spatial bias to the training quadrant. (controls spent most of time in training quadrant)
2) Did not affect visual discrimination learning.

Second experiment with two discriminable platforms, one was rigid and provided escape, other was floating and sank when rat attempted to climb on. Platforms were moved between several locations during training. Task was to learn to approach the rigid platform regardless of location.
Nonsignificant trend towards faster learning in controls but overall groups did not differ: i.e. AP5 effects unlikely to be mediated by a secondary sensorimotor or motivational impairment.

3) Examined LTP in vivo in a third set of rats. D,L-AP5 caused a total blockade of induction if LTP in vivo. Authors note that demonstration of blockade of LTP by D,L-AP5 does not prove that these phenomena are causally related.

Interesting background: hippocampal lesions also cause a marked impairment in place learning: thus AP5 produces a similar profile to hippocampal lesions but less severe.

Answer 1

Morris et al 1986

Question 2

‘the learning related increase in Fos-like immunoreactivity following training is transitory and hav localised the increase to a population of neurons immunopositive for GABA’.

Previous work has shown that after domestic chicks have learned the characteristics of an object (visual imprinting)- there is a learning-related increase in density of Fos-immunopositive neurons in the hyperstriatum ventral (forebrain)

Chicks trained by exposure, then killed, sections from imprinted chicks and controls examined

Relative to untrained chicks, there was a 60% increase in the number of Fos-positive nuclei in the hyperstriatum ventral 3h after start of training.

Approximately 95% of the Fos-positive neurons in the hyperstriatum ventral were also immunopositive for GABA.

Answer 2

McCabe and Horn

Question 3

Used fear-potentiated startle paradigm to measure aversive conditioning after intra-amygdala infusion fof the NMDA antagonist AP5.

• Infusion of AP5 immediately before noise-footshock parings dose-dependently blocked acquisition or consolidation of auditory fear-potentiated startle.
• Rats reacted normaly to footshocks, and showed reliable potentiated startle expression after pretesting AP5 at a dose that blocked acquisition

‘AP5 blocks acquisition acquisition but not expression of fear potentiated startle into an auditory controlled stimulus’

Answer 3

Davis, Campeau et al 1992

Question 4

Tested the ampakine CX717, a positive allosteric modulator of AMPA receptors, for its ability to enhance performance on a cognitive, delayed match-to sample task under normal circumstances in well trained monkeys, as well as alleviate the detrimental effects of 20-36 hours of sleep deprivation.

CX717 produced a dose-dependent enhancement of task performance under normal alert testing conditions.

• Concomitant measures of regional cerebral metabolic rates for glucose during the task (using PET) showed increased activity in PFC, dorsal striatum, medial temporal lobe- that was significantly enhanced over normal alert conditions following administration of CX717.

Single night of sleep deprivation produced severe impairment in monkeys, accompanied by significant alterations in task-related CMR in these same brain regions.

• However, CX717 produced a striking removal of the behavioral impairment, returned performance to above-normal levels even though animals were sleep deprived. Also returned all but one brain region affected by sleep deprivation to normal alert pattern.

Answer 4

Porrino et al 2006

Question 5

Review: Benzodiazepines, memory and mood.

BZs impair certain aspects of human memory functions- produce an apparent anterograde amnesia, also affect mood states ny reducing anxiety and inducing sedation.

NB Benzodiazepines potentiate the action of the GABA receptor (GABA being the main inhibitory NT in the brain)

Answer 5

Curran 1990