RESUMEN
Resilience to stress is critical for the development of depression. Enhanced adenosine A1 receptor (A1R) signaling mediates the antidepressant effects of acute sleep deprivation (SD). However, chronic SD causes long-lasting upregulation of brain A1R and increases the risk of depression. To investigate the effects of A1R on mood, we utilized two transgenic mouse lines with inducible A1R overexpression in forebrain neurons. These two lines have identical levels of A1R increase in the cortex, but differ in the transgenic A1R expression in the hippocampus. Switching on the transgene promotes robust antidepressant and anxiolytic effects in both lines. The mice of the line without transgenic A1R overexpression in the hippocampus (A1Hipp-) show very strong resistance towards development of stress-induced chronic depression-like behavior. In contrast, the mice of the line in which A1R upregulation extends to the hippocampus (A1Hipp+), exhibit decreased resilience to depression as compared to A1Hipp-. Similarly, automatic analysis of reward behavior of the two lines reveals that depression resistant A1Hipp-transgenic mice exhibit high sucrose preference, while mice of the vulnerable A1Hipp + line developed stress-induced anhedonic phenotype. The A1Hipp + mice have increased Homer1a expression in hippocampus, correlating with impaired long-term potentiation in the CA1 region, mimicking the stressed mice. Furthermore, virus-mediated overexpression of Homer1a in the hippocampus decreases stress resilience. Taken together our data indicate for first time that increased expression of A1R and Homer1a in the hippocampus modulates the resilience to stress-induced depression and thus might potentially mediate the detrimental effects of chronic sleep restriction on mood.
Asunto(s)
Corteza Cerebral/metabolismo , Depresión/genética , Hipocampo/metabolismo , Proteínas de Andamiaje Homer/genética , Receptor de Adenosina A1/genética , Resiliencia Psicológica , Privación de Sueño/metabolismo , Estrés Psicológico/genética , Animales , Conducta Animal , Región CA1 Hipocampal/metabolismo , Depresión/metabolismo , Depresión/psicología , Prueba de Laberinto Elevado , Potenciales Postsinápticos Excitadores , Suspensión Trasera , Proteínas de Andamiaje Homer/metabolismo , Potenciación a Largo Plazo/genética , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Prueba de Campo Abierto , Prosencéfalo , Receptor de Adenosina A1/metabolismo , Recompensa , Privación de Sueño/psicologíaRESUMEN
Conventional antidepressants have limited efficacy and many side effects, highlighting the need for fast-acting and specific medications. Induction of the synaptic protein Homer1a mediates the effects of different antidepressant treatments, including the rapid action of ketamine and sleep deprivation (SD). We show here that mimicking Homer1a upregulation via intravenous injection of cell-membrane-permeable TAT-Homer1a elicits rapid antidepressant effects in various tests. Similar to ketamine and SD, in vitro and in vivo application of TAT-Homer1a enhances mGlu5 signaling, resulting in increased mTOR pathway phosphorylation, and upregulates synaptic AMPA receptor expression and activity. The antidepressant action of SD and Homer1a induction depends on mGlu5 activation specifically in excitatory CaMK2a neurons and requires enhanced AMPA receptor activity, translation, and trafficking. Moreover, our data demonstrate a pronounced therapeutic potential of different TAT-fused peptides that directly modulate mGlu5 and AMPA receptor activity and thus might provide a novel strategy for rapid and effective antidepressant treatment.
