ABSTRACT
In recent years it has become clear that corticosteroid hormones (such as corticosterone) are released in ultradian pulses as a natural consequence of pituitary-adrenal interactions. All organs, including the brain, are thus exposed to pulsatile changes in corticosteroid hormone level, important to ensure full genomic responsiveness to stress-induced surges. However, corticosterone also changes neuronal excitability through rapid non-genomic pathways, particularly in the hippocampus. Potentially, background excitability of hippocampal neurons could thus be changed by pulsatile exposure to corticosteroids. It is currently unknown, though, how neuronal activity alters during a sequence of corticosterone pulses. To test this, hippocampal cells were exposed in vitro to four consecutive corticosterone pulses with a 60 min inter-pulse interval. During the pulses we examined four features of hippocampal signal transfer by the main excitatory transmitter glutamate-i.e., postsynaptic responses to spontaneous release of presynaptic vesicles, postsynaptic GluA2-AMPA receptor dynamics, basal (evoked) field responses, and synaptic plasticity, using a set of high resolution imaging and electrophysiological approaches. We show that the first pulse of corticosterone causes a transient increase in miniature EPSC frequency, AMPA receptor trafficking and synaptic plasticity, while basal evoked field responses are unaffected. This pattern is not maintained during subsequent applications: responses become more variable, attenuate or even reverse over time, albeit with different kinetics for the various experimental endpoints. This may indicate that the beneficial effect of ultradian pulses on transcriptional regulation in the hippocampus is not consistently accompanied by short-term perturbations in background excitability. In general, this could be interpreted as a means to keep hippocampal neurons responsive to incoming signals related to environmental challenges.
Subject(s)
Corticosterone/pharmacology , Evoked Potentials/drug effects , Excitatory Postsynaptic Potentials/drug effects , Hippocampus/drug effects , Neurons/drug effects , Animals , Coculture Techniques , Corticosterone/metabolism , Embryo, Mammalian , Evoked Potentials/physiology , Excitatory Postsynaptic Potentials/physiology , Gene Expression , Hippocampus/cytology , Hippocampus/physiology , Kinetics , Male , Mice , Mice, Inbred C57BL , Microtomy , Molecular Imaging , Neuroglia/cytology , Neuroglia/drug effects , Neuroglia/physiology , Neuronal Plasticity/physiology , Neurons/cytology , Neurons/physiology , Primary Cell Culture , Protein Transport , Quantum Dots , Rats , Rats, Sprague-Dawley , Receptors, AMPA/genetics , Receptors, AMPA/metabolism , Synaptic Vesicles/drug effects , Synaptic Vesicles/physiology , Tissue Culture TechniquesABSTRACT
The rodent adrenal hormone corticosterone (CORT) reaches the brain in hourly ultradian pulses, with a steep rise in amplitude before awakening. The impact of a single CORT pulse on glutamatergic transmission is well documented, but it remains poorly understood how consecutive pulses impact on glutamate receptor trafficking and synaptic plasticity. By using high-resolution imaging and electrophysiological approaches, we report that a single pulse of CORT to hippocampal networks causes synaptic enrichment of glutamate receptors and increased responses to spontaneously released glutamatergic vesicles, collectively abrogating the ability to subsequently induce synaptic long-term potentiation. Strikingly, a second pulse of CORT one hour after the first--mimicking ultradian pulses--completely normalizes all aspects of glutamate transmission investigated, restoring the plastic range of the synapse. The effect of the second pulse is precisely timed and depends on a nongenomic glucocorticoid receptor-dependent pathway. This normalizing effect through a sequence of CORT pulses--as seen around awakening--may ensure that hippocampal glutamatergic synapses remain fully responsive and able to encode new stress-related information when daily activities start.
Subject(s)
Corticosterone/administration & dosage , Corticosterone/physiology , Glutamic Acid/physiology , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Activity Cycles/physiology , Animals , Cells, Cultured , Hippocampus/drug effects , Hippocampus/physiology , Long-Term Potentiation/drug effects , Long-Term Potentiation/physiology , Male , Mice , Mice, Inbred C57BL , Rats , Receptors, AMPA/drug effects , Receptors, AMPA/physiology , Receptors, Glucocorticoid/drug effects , Receptors, Glucocorticoid/physiologyABSTRACT
Stress causes the release of many transmitters and hormones, including corticosteroids. These molecules enter the brain and exert their effects through the mineralo- and glucocorticoid receptor. The former receptor plays an important role in neuronal stability. However, it also mediates rapid non-genomic corticosteroid effects that in synergy with other stress mediators activate limbic cells and promote behavioral choices allowing the organism to quickly respond to the imminent danger. Glucocorticoid receptors primarily mediate slow genomic effects, for instance in the hippocampus and prefrontal cortex, which are thought to contribute to contextual and higher cognitive aspects of behavioral performance several hours after stress. Rapid and slow effects interact and collectively contribute to successful behavioral adaptation. Long-term disturbances in the release pattern of corticosteroid hormones and in the responsiveness of their receptors give rise to structural and functional changes in neuronal properties which may contribute to the expression of psychopathology.
