RGS14₄₁₄ treatment induces memory enhancement and rescues episodic memory deficits

Abstract

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

RGS14 Regulation of Post-Synaptic Signaling and Spine Plasticity in Brain

“…Lentiviral expression of RGS 414 , in layer six of the V2 visual cortex of rats, enhances object recognition memory and permits long-term memory of a novel object months after initial exposure [167]. In a separate report, the introduction of RGS 414 into area CA1 of rats enhanced neurite formation and branching in area CA1 pyramidal cells, which was dependent on increases in BDNF production [166]. RGS 414 expression in CA1 also enhanced Y-maze and MWM performance in adult, aged, and AD-model rats.…”

“…A truncated form of human RGS14 (RGS 414 ) has been investigated for its effects on rodent behavior linked to hippocampal memory [166,167]. Lentiviral expression of RGS 414 , in layer six of the V2 visual cortex of rats, enhances object recognition memory and permits long-term memory of a novel object months after initial exposure [167].…”

14‐3‐3ζ is crucial for the conversion of labile short‐term object recognition memory into stable long‐term memory

“…Western blotting was performed as described previously (Khan et al., 1993; Masmudi‐Martín et al., 2019). A 4‐mm punch specimen was extracted from the injected area of the rat brain and homogenized in 100 mM Tris‐HCl buffer, pH 8.0, with 1% protease inhibitor cocktail and 1% phosphatase inhibitor cocktail (both from Sigma‐Aldrich).…”

“…AAV encoding control shRNA was also obtained from GeneCopoeia (Heidelberg, Germany; catalog number AC202). The rats were injected stereotaxically with 1 × 10 10 GC AAV‐14‐3‐3ζ shRNA or AAV‐control shRNA in a volume of 2 μl into the bilateral PRh at coordinates similar to those described above for lentivirus delivery and similar to earlier where same coordinates and injection volume were used, the protein expression was observed within the limit of the PRh area (Masmudi‐Martín et al., 2019). Seven days after the injection, both groups of shRNA rats were injected with lentivirus carrying the RGS14 414 gene as described above for lentivirus delivery.…”

“…Quantitative RT‐PCR (qRT‐PCR) was performed similar to as described earlier (Masmudi‐Martín et al., 2019). A 4 mm punch was extracted from the injected area of the rat brain.…”