RESUMEN
BACKGROUND: NYX-2925 is a novel N-methyl-D-aspartate receptor (NMDAR) modulator that has been shown to facilitate both NMDAR-dependent long-term potentiation (LTP) in vitro and learning and memory in vivo. OBJECTIVE: The present studies examine the effects of NYX-2925 on NMDAR-dependent auditory LTP (aLTP) in vivo. METHODS: NMDAR-dependent aLTP and NMDAR-dependent auditory mismatch negativity (MMN) was measured, as well as changes in resting-state qEEG power. RESULTS: NYX-2925 (1, 10 mg/kg PO) increased aLTP 1 h after auditory tetanus measured by the post- minus pre-tetanus difference waveform 140-180 ms post tone onset. NYX-2925 (0.1, 1 mg/kg PO) facilitated MMN measured by the difference waveform (i.e., deviant minus standard tones). NYX-2925 (0.1, 1, 10 mg/kg PO) also enhanced resting-state alpha qEEG power. Conversely, the NMDAR glutamate site antagonist CPP (10 mg/kg IP) reduces alpha power and MMN and produces an opposite effect as NYX-2925 on aLTP. CONCLUSIONS: Together, these data suggest that the activation of the NMDAR by NYX-2925 enhances synaptic plasticity in vivo, which may both reduce symptoms of neurological disorders and serve as a biomarker for drug effects. This is the first demonstration of a long-lasting (1-h post-tetanus) effect of NMDAR modulation on synaptic plasticity processes in vivo using a noninvasive technique in freely behaving animals.
Asunto(s)
Electroencefalografía/métodos , Plasticidad Neuronal/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , Compuestos de Espiro/farmacología , Investigación Biomédica Traslacional/métodos , Animales , Electroencefalografía/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Plasticidad Neuronal/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistasRESUMEN
In patients suffering from post-traumatic stress disorder (PTSD), fear evoked by trauma-related memories lasts long past the traumatic event and it is often complicated by general anxiety and depressed mood. This poses a treatment challenge, as drugs beneficial for some symptoms might exacerbate others. For example, in preclinical studies, antagonists of the NR2B subunit of N-methyl-d-aspartate receptors and activators of cAMP-dependent protein kinase (PKA) act as potent antidepressants and anxiolytics, but they block fear extinction. Using mice, we attempted to overcome this problem by interfering with individual NR2B and PKA signaling complexes organized by scaffolding proteins. We infused cell-permeable Tat peptides that displaced either NR2B from receptor for activated C kinase 1 (RACK1), or PKA from A-kinase anchor proteins (AKAPs) or microtubule-associated proteins (MAPs). The infusions were targeted to the retrosplenial cortex, an area involved in both fear extinction of remotely acquired memories and in mood regulation. Tat-RACK1 and Tat-AKAP enhanced fear extinction, all peptides reduced anxiety and none affected baseline depression-like behavior. However, disruption of PKA complexes distinctively interfered with the rapid antidepressant actions of the N-methyl-D-aspartate receptors antagonist MK-801 in that Tat-MAP2 blocked, whereas Tat-AKAP completely inverted the effect of MK-801 from antidepressant to depressant. These effects were unrelated to the MK-801-induced changes of brain-derived neurotrophic factor messenger RNA levels. Together, the findings suggest that NR2B-RACK1 complexes specifically contribute to fear extinction, and may provide a target for the treatment of PTSD. AKAP-PKA, on the other hand, appears to modulate fear extinction and antidepressant responses in opposite directions.