Marianne Fillenz Annual Lecture 2019

Several lines of evidence, including recent GWAS, have suggested that schizophrenia may be a disorder of impaired synaptic plasticity, particularly in the hippocampus. Traditionally, hippocampal synaptic plasticity (e.g. long-term potentiation) has been thought to subserve the formation of associative memories. Yet schizophrenic subjects are often considered to be more, rather than less, likely to form associations, which is thought to underlie the generation of their false beliefs and delusions. I will present data showing that ablating key glutamate receptor subunits involved in hippocampal synaptic plasticity (and implicated in schizophrenia) leads to deficits in a form of non-associative short-term memory that underlies the habituation of attention. This generates aberrant salience, hyperdopaminergic responses and increased theta coherence, and an increased (rather than decreased) propensity to form associations, reminiscent of what is seen in schizophrenic patients. The implications of these results for understanding synaptic homeostasis during sleep will also be discussed.