The mechanisms underlying memory loss associated with Alzheimer’s disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of genes encoding chaperones that localize to the endoplasmic reticulum (ER). These chaperones fold and traffic plasticity-related proteins to the cell surface during long-lasting forms of synaptic plasticity and memory. Dysregulation of Nr4a transcription factors and ER chaperones is linked to ADRD, and overexpressing Nr4a1 or the chaperone Hspa5 ameliorates long-term memory deficits in a tau-based mouse model of ADRD, pointing toward innovative therapeutic approaches for treating memory loss. Our findings establish a unique molecular concept underlying long-term memory and provide insights into the mechanistic basis of cognitive deficits in dementia.

The mechanisms underlying memory loss associated with Alzheimers disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of a group of genes encoding chaperones that localize to the endoplasmic reticulum (ER), which function to traffic plasticity-related proteins to the cell surface during long lasting forms of synaptic plasticity and memory. Nr4a transcription factors and ER chaperones are linked to ADRD in human samples as well as mouse models, and overexpressing Nr4a1 or the ER chaperone Hspa5 ameliorates the long-term memory deficits in a tau-based mouse model of ADRD, pointing towards novel therapeutic approaches for treating memory loss. Thus, our findings establish protein folding in the ER as a novel molecular concept underlying long-term memory, providing new insights into the mechanistic basis of cognitive deficits in dementia.

Memory consolidation involves discrete patterns of transcriptional events in the hippocampus. Despite the emergence of single-cell transcriptomic profiling techniques, defining learning-responsive gene expression across subregions of the hippocampus has remained challenging. Here, we utilized unbiased spatial sequencing to elucidate transcriptome-wide changes in gene expression in the hippocampus following learning, enabling us to define molecular signatures unique to each hippocampal subregion. We find that each subregion of the hippocampus exhibits distinct yet overlapping transcriptomic signatures. Although the CA1 region exhibited increased expression of genes related to transcriptional regulation, the DG showed upregulation of genes associated with protein folding. We demonstrate the functional relevance of subregion-specific gene expression by genetic manipulation of a transcription factor selectively in the CA1 hippocampal subregion, leading to long-term memory deficits. This work demonstrates the power of using spatial molecular approaches to reveal transcriptional events during memory consolidation.

Characterization of brain-enriched lncRNAs have predominantly been restricted to the nuclear compartment; with limited exploration of synaptic lncRNA functions. Our RNA-seq analysis of synaptoneurosomes identify 94 synaptically-enriched lncRNAs in the adult mouse hippocampus. Among these, we characterized the roles of Pantr1, Pvt1 and 2410006H16Rik (named SynLAMP) in glutamatergic synapse development, plasticity and memory. Pvt1 regulates dendritic arborization, spine morphology and glutamatergic synapse formation via a molecular framework of synaptogenic genes; as detected by RNA-seq analysis of the hippocampal trancriptome following Pvt1 knockdown. SynLAMP and Pantr1 modulate mEPSC amplitude and surface AMPA receptor distribution in mature synapses. We find activity-invoked redistribution of these synaptic lncRNAs and their concommitant reversible association with RNA binding proteins. The activity-dependent, transcript-specific synaptic localization of SynLAMP and Pantr1 indicate their synapse-centric function. SynLAMP specifically regulates basal and activity-invoked nascent translation in somato-dendritic compartments and its RNAi disrupts memory consolidation, underlining its input-specific role in synaptic translation.