RESUMEN
BACKGROUND: Long-term synaptic plasticity is a basic ability of the brain to dynamically adapt to external stimuli and regulate synaptic strength and ultimately network function. It is dysregulated by behavioral stress in animal models of depression and in humans with major depressive disorder. Antidepressants have been shown to restore disrupted synaptic plasticity in both animal models and humans; however, the underlying mechanism is unclear. METHODS: We examined modulation of synaptic plasticity by selective serotonin reuptake inhibitors (SSRIs) in hippocampal brain slices from wild-type rats and serotonin transporter (SERT) knockout mice. Recombinant voltage-gated calcium (Ca2+) channels in heterologous expression systems were used to determine the modulation of Ca2+ channels by SSRIs. We tested the behavioral effects of SSRIs in the chronic behavioral despair model of depression both in the presence and in the absence of SERT. RESULTS: SSRIs selectively inhibited hippocampal long-term depression. The inhibition of long-term depression by SSRIs was mediated by a direct block of voltage-activated L-type Ca2+ channels and was independent of SERT. Furthermore, SSRIs protected both wild-type and SERT knockout mice from behavioral despair induced by chronic stress. Finally, long-term depression was facilitated in animals subjected to the behavioral despair model, which was prevented by SSRI treatment. CONCLUSIONS: These results showed that antidepressants protected synaptic plasticity and neuronal circuitry from the effects of stress via a modulation of Ca2+ channels and synaptic plasticity independent of SERT. Thus, L-type Ca2+ channels might constitute an important signaling hub for stress response and for pathophysiology and treatment of depression.
Asunto(s)
Antidepresivos/uso terapéutico , Canales de Calcio Tipo L/metabolismo , Proteínas de Unión al ARN/metabolismo , Estrés Psicológico/tratamiento farmacológico , Transmisión Sináptica/efectos de los fármacos , Factores de Edad , Animales , Células CHO , Cloruro de Cadmio/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/genética , Cricetulus , Modelos Animales de Enfermedad , Estimulación Eléctrica , Femenino , Fluvoxamina/uso terapéutico , Células HEK293 , Suspensión Trasera/psicología , Hipocampo/citología , Humanos , Técnicas In Vitro , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Nifedipino/farmacología , Paroxetina/farmacología , Técnicas de Placa-Clamp , Piperazinas/farmacología , Piridinas/farmacología , Proteínas de Unión al ARN/genética , Ratas , Ratas Transgénicas , Ratas Wistar , Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Estrés Psicológico/genética , Natación/psicología , Transmisión Sináptica/genética , TransfecciónRESUMEN
There exists substantial evidence that some forms of explicit learning in mammals require long-term potentiation (LTP) at hippocampal CA3-CA1 synapses. While CA1 LTP has been well characterized at the monosynaptic level, it still remains unclear how the afferent systems to the hippocampus can initiate formation of this neuroplastic phenomenon. Using voltage-sensitive dye imaging (VSDI) in a mouse brain slice preparation, we show that evoked entorhinal cortical (EC) theta-frequency input to the dentate gyrus highly effectively generates waves of neuronal activity which propagate through the entire trisynaptic circuit of the hippocampus ("HTC-Waves"). This flow of activity, which we also demonstrate in vivo, critically depends on frequency facilitation of mossy fiber to CA3 synaptic transmission. The HTC-Waves are rapidly boosted by the cognitive enhancer caffeine (5 µM) and the stress hormone corticosterone (100 nM). They precisely follow the rhythm of the EC input, involve high-frequency firing (>100 Hz) of CA3 pyramidal neurons, and induce NMDA receptor-dependent CA1 LTP within a few seconds. Our study provides the first experimental evidence that synchronous theta-rhythmical spiking of EC stellate cells, as occurring during EC theta oscillations, has the capacity to drive induction of CA1 LTP via the hippocampal trisynaptic pathway. Moreover, we present data pointing to a basic filter mechanism of the hippocampus regarding EC inputs and describe a methodology to reveal alterations in the "input-output relationship" of the hippocampal trisynaptic circuit.
RESUMEN
The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we determined that CRHR1 is expressed in forebrain glutamatergic and γ-aminobutyric acid-containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.
Asunto(s)
Ansiedad , Dopamina/metabolismo , Ácido Glutámico/metabolismo , Neuronas/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Amígdala del Cerebelo/metabolismo , Animales , Conducta Animal , Hormona Liberadora de Corticotropina/metabolismo , Miedo , Hipocampo/metabolismo , Masculino , Memoria , Mesencéfalo , Ratones , Ratones Noqueados , Actividad Motora , Corteza Prefrontal/metabolismo , Prosencéfalo/citología , Prosencéfalo/metabolismo , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/genética , Transmisión Sináptica , Área Tegmental Ventral/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Corticotropin-releasing hormone (CRH) is thought to play an important role in the pathophysiology of stress-related psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). However, knowledge about the actions of CRH at the neuronal network level is only scarce. Here, we examined whether CRH affects neuronal activity propagation through the hippocampal formation (HF), a brain region which is likely to be involved in MDD and PTSD. For this purpose, we applied voltage-sensitive dye imaging (VSDI) to specifically cut hippocampal brain slices obtained from adult mice. This approach allowed us to investigate evoked neuronal activity propagation through the HF with micrometer spatial and millisecond temporal resolution. Application of CRH (50 nM) to slices increased neuronal activity propagation from the dentate gyrus (DG) to the CA1 subfield. This effect of CRH was caused by amplification of neuronal excitation on its passage through the HF and absent in mice lacking the CRH receptor type 1 (CRHR1). In conclusion, our study presents a VSDI assay for the investigation of neuronal activity propagation through the HF and demonstrates that CRH, via CRHR1, enhances this activity propagation. This effect of CRH might contribute to alterations of memory formation seen in MDD and PTSD. Moreover, it could influence hippocampal regulation of hypothalamic-pituitary-adrenal axis (HPA-axis) activity.