The role of impaired synaptic plasticity in aberrant salience

Hippocampal network dysfunction has been recognised as a potential pathway to psychotic symptoms for many years. Reduced hippocampal synaptic plasticity is a core feature in a diverse range of conditions, from Alzheimer’s Disease to depression and schizophrenia, and may explain overlap in symptom domains across these disorders.
This thesis has investigated cognitive impairments in mouse models relevant to schizophrenia, in the context of their known effects on synaptic plasticity; integrating these effects into a psychological framework for associative learning and attention. Hippocampal long-term potentiation requires finely balanced tuning of glutamatergic signalling via expression of NMDA and AMPA receptors at the synapse. We manipulated this balance by genetic knockout of the AMPA receptor subunit GluA1, or through pharmacological blockade of the NMDA receptor with MK-801. Additionally, we investigated the effect of increased dopamine transmission, also heavily implicated in schizophrenia, by acute administration of amphetamine.
Through extensive motor and cognitive profiling, we revealed divergent behavioural phenotypes dependent on the circuit manipulation. Glutamatergic dysfunction induced significant locomotor hyperactivity and impaired short-term habituation, but when investigated in more detail we saw increased responding specifically to repeatedly presented stimuli; indicative of stimulus-specific sensitisation. While amphetamine also induced hyperactivity, this was stimulus-independent and appeared to reflect general increases in arousal and attention regardless of environment.
We then went on to investigate how these deficits in habituation affect attentional processing in the 5-choice serial reaction time test. All treatment groups showed unique behavioural abnormalities in tests of attention. The increased arousal following amphetamine treatment was observed here again, to the point that animals were impaired in their ability to respond appropriately. MK-801 seemingly induced global deficits in attention that impaired an animals’ ability to attend to the task, whereas GluA1 knockout left attending largely intact until conditions were made unpredictable.
Finally we investigated how impaired short-term habituation and attentional processes in GluA1-/- mice affect their ability to accurately form associations using sensory preconditioning. Mice lacking GluA1 showed enhanced performance in this task under simple conditions, indicating an increased propensity to form associations. When conditions were more complex, however, they were impaired. These data suggest maladaptive associative learning in GluA1-/- that can be beneficial or harmful to learning, depending on the circumstances.
These findings show that perturbations of glutamate transmission affect an individual’s ability to accurately learn about their environment and suggest a mechanism through which this actually leads to sensitisation to recently familiar stimuli as a result of deficits in short-term habituation. The impact of this impairment on associative learning indicates a critical role for hippocampal long-term potentiation in this mechanism, and also suggests that GluA1-/- share construct validity with clinical psychosis.

Advisor: Bannerman, D
Walton, M