Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells

Abstract

The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. These findings open a new avenue for the targeted erasure of episodic and contextual memories.

Adult Neurogenesis in the Songbird: Region-Specific Contributions of New Neurons to Behavioral Plasticity and Stability

“…It is interesting to note recent evidence that granule cells of the mouse dentate gyrus play a role in maintaining hippocampal memory traces [Madronal et al, 2016]. In this study, pharmacogenetic inhibition of dentate granule cells resulted in forgetting a learned association.…”

“…Moreover, the effect of transient inhibition was persistent, as the forgetting and reduced plasticity were seen both 1 and 5 days after granule cell inhibition. Thus, it seems that dentate granule cell activity was necessary for the maintenance of this hippocampal memory trace [Madronal et al, 2016].…”

Lost and found

“…Contrary to the predictions of interference views of forgetting, the same treatment potentiated new location learning, rather than impairing it. Parallel electrophysiological studies implicated depotentiation as a likely contributor to forgetting, just as Madronal et al (2016) suggest in their work.…”

“…Effective forgetting is also central to effective memory. Three new neurobiological papers have recently been published that highlight different aspects of forgetting (Madronal et al, 2016, Migues et al, 2016, Roy et al, 2016.…”

“…However, a drug is unlikely 'to do it on its own' without appropriate stimulation. In the same vein, Madronal et al (2016) and Migues et al (2016) emphasise that the 'devil-is-in-the-detail' with a respect to understanding activity-dependent forgetting. It is likely some way off, but these neurobiological studies raise, in different ways, the intriguing idea of rescuing long-term memory deficits, with a peptide or another engrambased approach, in a manner that takes account of this neuronal activity and selectivity.…”