Binding experience-relevant neuronal assemblies through disinhibition

Granule cells in the dentate gyrus (DGgc), a brain region important for spatial learning, are part of the engrams formed when an animal explores a new context. Previous work showed that modulation of DGgc activity by perisomatic inhibition bidirectionally regulates memory encoding. Whether this result is due to a differential recruitment of experience-relevant neuronal assemblies or the functional connectivity between them, is not yet known. We combined pharmacogenetic tools (DREADDs) to increase or decrease the activity of parvalbumin (PV)-interneurons in DG while mice encoded spatial information in the Novel Object Location task (NOL). Sixty min after memory encoding in the NOL task animals were sacrificed and their brains processed and quantified for c-Fos staining. Exploration in the NOL task induced a robust increase in the number of c-Fos+ cells across hippocampal subfields. However, the number of c-Fos+ cells, both in the hippocampus and extra-hippocampal structures like the medial prefrontal cortex (mPFC) and the nucleus accumbens, was constant regardless of the inhibitory tone in the DG. Only a moderate increase in c-Fos intensity per cell in DGgc was found in the PV-cell inhibition group. In contrast, we found a significant increase in the correlation between the number of c-Fos+ cells in all quantified neuronal assemblies during PV-inhibition, and a decrease during activation. Together, these data reveal a critical regulatory role of perisomatic inhibition in the dentate gyrus in binding experience-relevant neuronal assemblies in memory.

Modulation of coordinated activity across cortical layers by plasticity of inhibitory synapses onto layer 5 pyramidal neurons

In the neocortex, synaptic inhibition shapes all forms of spontaneous and sensory-evoked activity. Importantly, inhibitory transmission is highly plastic, but the functional role of inhibitory synaptic plasticity is unknown. In the mouse barrel cortex, activation of layer 2/3 PNs elicited strong feed-forward perisomatic inhibition (FFI) onto layer 5 PNs. We found that FFI involving PV cells was strongly potentiated by postsynaptic PN burst firing. FFI plasticity modified PN excitation-to-inhibition (E/I) ratio, strongly modulated PN gain and altered information transfer across cortical layers. Moreover, our LTPi-inducing protocol modified the firing of layer 5 PNs and altered the temporal association of PN spikes to γ-oscillations both in vitro and in vivo. All these effects were captured by unbalancing the E/I ratio in a feed-forward inhibition circuit model. Altogether, our results indicate that activity-dependent modulation of perisomatic inhibitory strength effectively influences the participation of single principal cortical neurons to cognitive-relevant network activity.Impact StatementLong-term potentiation of feed-forward perisomatic inhibition effectively alters the computational properties of single layer 5 pyramidal neurons and their association to network activity.