Cellular responses in the V2 secondary visual cortex to simple as well as complex visual stimuli have been well studied. However, the role of area V2 in visual memory remains unexplored. We found that layer 6 neurons of V2 are crucial for the processing of object-recognition memory (ORM). Using the protein regulator of G protein signaling-14 (RGS-14) as a tool, we found that the expression of this protein into layer 6 neurons of rat-brain area V2 promoted the conversion of a normal short-term ORM that normally lasts for 45 minutes into long-term memory detectable even after many months. Furthermore, elimination of the same-layer neurons by means of injection of a selective cytotoxin resulted in the complete loss of normal as well as protein-mediated enhanced ORM.

Memory deficits affect a large proportion of the human population and are associated with aging and many neurologic, neurodegenerative, and psychiatric diseases. Treatment of this mental disorder has been disappointing because all potential candidates studied thus far have failed to produce consistent effects across various types of memory and have shown limited to no effects on memory deficits. Here, we show that the promotion of neuronal arborization through the expression of the regulator of G‐protein signaling 14 of 414 amino acids (RGS14414) not only induced robust enhancement of multiple types of memory but was also sufficient for the recovery of recognition, spatial, and temporal memory, which are kinds of episodic memory that are primarily affected in patients or individuals with memory dysfunction. We observed that a surge in neuronal arborization was mediated by up‐regulation of brain‐derived neurotrophic factor (BDNF) signaling and that the deletion of BDNF abrogated both neuronal arborization activation and memory enhancement. The activation of BDNF‐dependent neuronal arborization generated almost 2‐fold increases in synapse numbers in dendrites of pyramidal neurons and in neurites of nonpyramidal neurons. This increase in synaptic connections might have evoked reorganization within neuronal circuits and eventually supported an increase in the activity of such circuits. Thus, in addition to showing the potential of RGS14414 for rescuing memory deficits, our results suggest that a boost in circuit activity could facilitate memory enhancement and the reversal of memory deficits.—Masmudi‐Martín, M., Navarro‐Lobato, I., López‐Aranda, M. F., Delgado, G., Martín‐Montañez, E., Quiros‐Ortega, M. E., Carretero‐Rey, M., Narváez, L., Garcia‐Garrido, M. F., Posadas, S., López‐Téllez, J. F., Blanco, E., Jiménez‐Recuerda, I., Granados‐Durán, P., Paez‐Rueda, J., López, J. C., Khan, Z. U. RGS14414 treatment induces memory enhancement and rescues episodic memory deficits. FASEB J. 33, 11804‐11820 (2019). http://www.fasebj.org

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The remedy of memory deficits has been inadequate, as all potential candidates studied thus far have shown limited to no effects and a search for an effective strategy is ongoing. Here, we show that an expression of RGS14414 in rat perirhinal cortex (PRh) produced long-lasting object recognition memory (ORM) enhancement and that this effect was mediated through the upregulation of 14-3-3ζ, which caused a boost in BDNF protein levels and increase in pyramidal neuron dendritic arborization and dendritic spine number. A knockdown of the 14-3-3ζ gene in rat or the deletion of the BDNF gene in mice caused complete loss in ORM enhancement and increase in BDNF protein levels and neuronal plasticity, indicating that 14-3-3ζ-BDNF pathway-mediated structural plasticity is an essential step in RGS14414-induced memory enhancement. We further observed that RGS14414 treatment was able to prevent deficits in recognition, spatial, and temporal memory, which are types of memory that are particularly affected in patients with memory dysfunctions, in rodent models of aging and Alzheimer’s disease. These results suggest that 14-3-3ζ-BDNF pathway might play an important role in the maintenance of the synaptic structures in PRh that support memory functions and that RGS14414-mediated activation of this pathway could serve as a remedy to treat memory deficits.

The consolidation of new memories into long‐lasting memories is multistage process characterized by distinct temporal dynamics. However, our understanding on the initial stage of transformation of labile memory of recent experience into stable memory remains elusive. Here, with the use of rats and mice overexpressing a memory enhancer called regulator of G protein signaling 14 of 414 amino acids (RGS14414) as a tool, we show that the expression of RGS14414 in male rats' perirhinal cortex (PRh), which is a brain area crucial for object recognition memory (ORM), enhanced the ORM to the extent that it caused the conversion of labile short‐term ORM (ST‐ORM) expected to last for 40 min into stable long‐term ORM (LT‐ORM) traceable after a delay of 24 hr, and that the temporal window of 40 to 60 min after object exposure not only was key for this conversion but also was the time frame when a surge in 14‐3‐3ζ protein was observed. A knockdown of 14‐3‐3ζ gene abrogated both the increase in 14‐3‐3ζ protein and the formation of LT‐ORM. Furthermore, this 14‐3‐3ζ upregulation increased brain‐derived growth factor (BDNF) levels in the time frame of 60 min and 24 hr and 14‐3‐3ζ knockdown decreased the BDNF levels, and a deletion of BDNF gene produced loss in mice ability to form LT‐ORM. Thus, within 60 min of object exposure, 14‐3‐3ζ facilitated the conversion of labile ORM into stable ORM, whereas beyond the 60 min, it mediated the consolidation of the stable memory into long‐lasting ORM by regulating BDNF signaling.