AUTHOR=Munari Leonardo , Patel Vishwendra , Johnson Nicholas , Mariottini Chiara , Prabha Som , Blitzer Robert D. , Iyengar Ravi TITLE=Memory discrimination is promoted by the expression of the transcription repressor WT1 in the dentate gyrus JOURNAL=Frontiers in Behavioral Neuroscience VOLUME=17 YEAR=2023 URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2023.1130840 DOI=10.3389/fnbeh.2023.1130840 ISSN=1662-5153 ABSTRACT=

The hippocampus is critical for the precise formation of contextual memories. Overlapping inputs coming from the entorhinal cortex are processed by the trisynaptic pathway to form distinct memories. Disruption in any step of the circuit flow can lead to a lack of memory precision, and to memory interference. We have identified the transcriptional repressor Wilm’s Tumor 1 (WT1) as an important regulator of synaptic plasticity involved in memory discrimination in the hippocampus. In male mice, using viral and transgenic approaches, we showed that WT1 deletion in granule cells of the dentate gyrus (DG) disrupts memory discrimination. With electrophysiological methods, we then identified changes in granule cells’ excitability and DG synaptic transmission indicating that WT1 knockdown in DG granule cells disrupts the inhibitory feedforward input from mossy fibers to CA3 by decreasing mIPSCs and shifting the normal excitatory/inhibitory (E/I) balance in the DG → CA3 circuit in favor of excitation. Finally, using a chemogenetic approach, we established a causal link between granule cell hyperexcitability and memory discrimination impairments. Our results suggest that WT1 enables a circuit-level computation that drives pattern discrimination behavior.