INVESTIGATING CIRCUIT AND SYNAPTIC MECHANISMS OF WORKING MEMORY DEFICITS IN A SCHIZOPHRENIA MOUSE MODEL

Working memory is essential for higher cognitive functions and is among the earliest symptoms in psychiatric disorders, including schizophrenia. Despite the importance, the neural mechanisms supporting working memory remain incompletely understood. Computational models have proposed short-term synaptic plasticity as a potential mechanism for transient information maintenance; however, how alterations in short-term plasticity contribute to working memory deficits in diseases remain unclear.
Here, we investigate working memory deficits using LgDel mice, a model of 22q11.2 microdeletion syndrome, the strongest known genetic risk factor for schizophrenia. We focus on the medial prefrontal cortex (mPFC)–mediodorsal thalamus (MD) circuit, which is critically involved in working memory.
Behavioral assessment using spontaneous alternation in Y-maze revealed reduced working memory performance in LgDel mice compared to control littermates.
Structural analyses using anterograde and retrograde circuit tracing are ongoing and aim to identify potential structural alterations within the mPFC–MD pathway. Preliminary measurements indicate a reduced bregma–lambda distance in LgDel mice, suggesting possible alteration in brain development.
To directly assess synaptic function, we are performing brain slice electrophysiology with optogenetic stimulation of mPFC–MD projections. These ongoing experiments aim to characterize short-term synaptic dynamics in LgDel mice and determine how synaptic alterations relate to observed behavioral deficits.
Together, this work aims to link short-term plasticity to circuit dysfunction underlying working memory impairment in schizophrenia.