The Role of the GluA1 AMPA Receptor Subunit and Hippocampal NMDA Receptors in Learning and Memory

Abstract

AMPA and NMDA receptors for glutamate are required for long-term potentiation (LTP) of synapses, proposed to be the neural basis of learning, particularly within the hippocampus. Glutamate dysfunction has also been linked to disorders including schizophrenia. The aim of this thesis is to investigate the role of glutamate dysfunction in learning and memory, using two transgenic mouse strains.
Gria1–/– mice lack the GluA1 subunit of the AMPA receptor and have impaired short-term memory for recently experienced stimuli, but intact long-term memory based on associative retrieval. Contrary to expectation, the experiments in this thesis suggest that the GluA1 subunit is required for cue-competition, but only when dependent on the level of generalisation between the cues. Despite short-term memory being impaired in Gria1–/– mice, flavour preference learning proposed to be dependent on short-term memory, was found to be intact. Learning about the relative reinforcement rates of levers was also normal, shown in the form of intact matching behaviour. In line with previous findings, mean lick cluster sizes, a measure of palatability, were impaired. Grin1ΔDGCA1 mice lack NMDA receptors specifically within the hippocampus. Flavour preference learning and matching behaviour were found to be normal, but mean lick cluster sizes were impaired. Both the Gria1–/– and Grin1ΔDGCA1 mice also showed enhanced reversal of matching behaviour compared to the control mice.
The results from this thesis provide further support for glutamate dependent synaptic plasticity not being required for associative learning. Glutamate may however be involved in other aspects of stimulus processing, including perceived hedonic value and sensitivity to the current temporal context. The precise mechanisms for these however remain unclear.