Abstract
Increasing evidence supports a model whereby memories are encoded by sparse ensembles of neurons called engrams, activated during memory encoding and reactivated upon recall. An engram consists of a network of cells that undergo long-lasting modifications of their transcriptional programs and connectivity. Ground-breaking advancements in this field have been made possible by the creative exploitation of the characteristic transcriptional responses of neurons to activity, allowing both engram labeling and manipulation. Nevertheless, numerous aspects of engram cell-type composition and function remain to be addressed. As recent transcriptomic studies have revealed, memory encoding induces persistent transcriptional and functional changes in a plethora of neuronal subtypes and non-neuronal cells, including glutamatergic excitatory neurons, GABAergic inhibitory neurons, and glia cells. Dissecting the contribution of these different cellular classes to memory engram formation and activity is quite a challenging yet essential endeavor. In this review, we focus on the role played by the GABAergic inhibitory component of the engram through two complementary lenses. On one hand, we report on available physiological evidence addressing the involvement of inhibitory neurons to different stages of memory formation, consolidation, storage and recall. On the other, we capitalize on a growing number of transcriptomic studies that profile the transcriptional response of inhibitory neurons to activity, revealing important clues on their potential involvement in learning and memory processes. The picture that emerges suggests that inhibitory neurons are an essential component of the engram, likely involved in engram allocation, in tuning engram excitation and in storing the memory trace.
Highlights
Specialty section: This article was submitted to Neuroplasticity and Development, a section of the journal Frontiers in Molecular Neuroscience
Four late-response genes (LRG) (Frmpd3, scl25a36, Kcna1, Ddhd1) were identified as induced in SOM+ neurons activated in vivo, and several of these have been suggested to be involved in excitatory synapse formation and stabilization. These results suggest that in excitatory and inhibitory neurons activity triggers a common set of immediate early genes (IEGs) which, in turn, elicit the expression of different combinations of LRGs resulting in subtype-specific synaptic responses to activity (Table 1)
It needs to be noted that, with a few recent exceptions, most of these investigations interrogated the transcriptional response of heterogenous brain areas to pharmacological or sensory stimulation, not to memoryinducing protocols
Summary
Higher cognitive functions such as learning, memory and processing of sensory perceptions, are strictly dependent on the correct flow of information within neuronal circuits made of both inhibitory and excitatory neurons. Stefanelli et al (2016) observed that optogenetic stimulation of sparse granule cells induces an increased GABAergic response onto the dendrites of surrounding granule cells This lateral inhibition of non-active principal cells relies on SOM+ interneurons activation and represents a mechanism to control engram size during formation of a memory trace. Activity-dependent expression of the IEG transcription factor NPAS4 in a subset of pyramidal neurons, selectively enhanced somatic inhibition mediated by CCKBCs, but not by PVBC (Hartzell et al, 2018) These studies emphasize the strategic functions of the inhibitory component of the engram in the early stages of memory formation. Activity-dependent induction in other cell types yes (EX_Emxl+) yes (EX_Emxl+) yes (EX_Emxl+) yes (EX_Emxl+) yes (EX_Emxl+) yes (EX_Emxl+) not in EX_Emxl+ not in EX_Emxl+ not in EX_Emxl+ not in EX_Emxl+ not in EX_Emxl+ no other cell type no other cell type not in EX_Emxl+ not in EX_Emxl+ not in EX_Emxl+ not in EX_Emxl+
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