TAT-GluR23Y

Rationale: Subanesthetic doses of ketamine have been reported to induce psychotic states that may mimic positive and negative symptoms as well as cognitive and memory deficits similar to those observed in schizophrenia. The cognitive and memory deficits are persistent, and their underlying cellular mechanisms remain unclear. Objectives: We sought to investigate the roles of dopamine D1/D5 receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in hippocampal synaptic transmission and spatial memory impairment induced by ketamine. Methods: We examined the effects of subanesthetic ketamine on hippocampal synaptic transmission in freely moving rats. Spatial memory was tested with the Morris water maze. Pretreatment with the D1/D5 receptors antagonist SCH23390 or the AMPA receptors endocytosis interfering peptide Tat-GluR23Y was conducted to examine their capacities to reverse ketamine-induced electrophysiological and behavioral alterations. A series of behavioral observations, including locomotion, prepulse inhibition, and social interaction, were also conducted after ketamine treatment. Results: Ketamine induced synaptic depression lasting at least 4 h at hippocampal Schaffer collateral-CA1 synapses in freely moving rats and long-term spatial memory impairment. Both the effects were blocked by either SCH23390 or Tat-GluR23Y. Ketamine also elicited transient behavioral changes lasting less than 90 min, such as hyperlocomotion and prepulse inhibition deficits. These changes were ameliorated by SCH23390 but not by Tat-GluR23Y. Rats treated with ketamine showed social withdrawal that was also attenuated by either SCH23390 or Tat-GluR23Y. Conclusions: Our results indicate that hippocampal synaptic depression is involved in ketamine-induced memory impairment, and this is modulated by D1/D5 receptors activation and AMPA receptors endocytosis.

Background: Glutamate neurotransmission stands as an important issue to minimize memory impairment. We investigated the effects of an inhibitor of α-amino-3-hydroxy-5-methyl-4-isozazole propionic acid receptors (AMPA) endocytosis and GluN2B subunit of N-methyl-d-aspartate receptors (NMDA), either isolated or combined, on memory impairments induced by Amyloid beta1-42 (Aβ). Methods: Eighty male Wistar rats were used for two experiments of consolidation and retrieval of memory. Memory impairment was induced by intracerebroventricular (ICV) injection of Aβ1-42 (2 μg/μl), and evaluated using Morris Water Maze (MWM). Each experiment consisted of 5 groups: Saline + Saline, Aβ + Saline, Aβ + Ifenprodil (Ifen, 3 nmol/ICV), Aβ +Tat-GluR23Y (3 µmol/kg/IP), and Aβ1 +Ifen + Tat-GluR23Y. Then, hippocampal cAMP-response element-binding protein (CREB) was measured by western blotting. Data were analyzed by Analysis of variance (ANOVA) repeated measure, and one-way Anova followed by Tukey's post hoc test. Results: During retrieval, Aβ+ Tat-GluR23Y showed significant improvement in total time spent (TTS) in the target quadrant (p = 0.009), escape latency to a platform (p = 0.008) and hippocampal level of CREB (p = 0.006) compared with Aβ + saline. Also, coadministration of Tat-GluR23Yand Ifen similar to Tat-GluR23Y alone caused significant improvement in TTS (p = 0.014) and latency to platform (p = 0.013). During consolidation, shorter escape latency (p = 0.001), longer TTS (p = 0.002) and higher level of hippocampal CREB were observed in the Aβ + Tat-GluR23Y (p = 0.001) and Aβ+ Tat-GluR23Y + Ifen (p = 0.017), respectively. Conclusion: The present study provides pieces of evidence that inhibition of AMPARs endocytosis using Tat-GluR23Y facilitates memory consolidation and retrieval in Aβ induced memory impairment via the CREB signaling pathway.

Alzheimer's disease (AD) is behaviorally characterized by memory impairments, and pathologically by amyloid β1-42 (Aβ1-42) plaques and tangles. Aβ binds to excitatory synapses and disrupts their transmission due to dysregulation of the glutamate receptors. Here we hypothesized that chronic inhibition of the endocytosis of AMPA receptors together with GluN2B subunit of NMDA receptors might improve cognition deficit induced by Aβ(1-42) neurotoxicity. Forty male Wistar rats were used in this study and divided into 5 groups: Saline + Saline, Aβ+Saline, Aβ+Ifen (Ifenprodil, 3 nmol /2 weeks), Aβ+GluR23Y (Tat-GluR23Y 3 μmol/kg/2 weeks) and Aβ+Ifen+GluR23Y (same doses and durations). Aβ(1-42) neurotoxicity was induced by intracerebroventricular (ICV) injection of Aβ1-42 (2 μg/μl/side), and then animals received the related treatments for 14 days. Cognitive performance of rats and hippocampal level of cAMP-response element-binding (CREB) were evaluated using Morris Water Maze (MWM), and western blotting respectively. Obtained data from the acquisition trials were analyzed by two way Anova and Student T test. Also one way Analysis of variance (ANOVA) with post hoc Tuckey were used to clarify between groups differences in probe test. The Group receiving Aβ, showed significant cognition deficit (long latency to platform and short total time spent in target quadrant (TTS), parallel with lower level of hippocampal CREB, versus vehicle group. While, Aβ+ GluR23Y exhibited the shortest latency to platform and the longest TTS during the probe test, parallel with the higher hippocampal level of CREB compared with other groups. The present study provides evidence that chronic administration of Tat-GluR23Y; an inhibitor of GluA2-AMPARs endocytosis, successfully restores spatial memory impaired by amyloid beta neurotoxicity targeting CREB signaling pathway.