Research articleCo-activation of both 5-HT1A and 5-HT7 receptors induced attenuation of glutamatergic synaptic transmission in the rat visual cortex
Introduction
As a neurotransmitter and neuromodulator, serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in the mammalian central nervous system (CNS) and mediates various physiological and pathophysiological brain functions, including motor activity, sleep–wakefulness cycles, cognition, sensory perception, mood, hormone secretion, nociception, spinal reflexes, sexual behavior and several psychiatric disorders [4,[18], [19], [20]]. The biological effects of 5-HT are mediated by at least 15 different 5-HT receptor subtypes located in the cell membrane, which are divided into seven distinct subfamilies designated 5-HT1 to 5-HT7 [20]. With the exception of 5-HT3 receptor (a serotonin-gated ion channel), all of these receptors are G protein-coupled receptors to activate downstream pathways and elicit their physiological effects [7].
It has been reported that 5-HT is released by fibers arising from raphe nuclei and play an important role in cognitive functions such as learning and memory in different regions of CNS, such as thalamus, hypothalamus, hippocampus, striatum and cortex [14,20]. Interestingly, the 5-HT1A receptors and 5-HT7 receptors exerted opposing effects in the modulation of fear learning, which indicated the importance of both 5-HT receptor subtypes and their signaling interaction in the regulation of emotional learning [6]. Learning involves dynamic changes in functioning and/or AMPA receptor membrane expression. Changes in postsynaptic AMPA receptors have been implicated in synaptic plasticity and learning and memory [9]. Some studies have examined the ability of 5-HT receptors to modulate AMPA receptor activity and affect synaptic transmission by activation of different 5-HT receptor subtypes. For example, 5-HT1A receptor activation inhibited AMPA-mediated synaptic current in the rat hippocampus and prefrontal cortex [1,3]. Selective blockade of 5HT1A receptors enhanced the phosphorylation level and membrane expression of the GluR1 subunit of AMPA receptors in hippocampal CA1 pyramidal neurons [17]. In contrast, the activation of postsynaptic 5-HT7 receptors enhanced the amplitude of the AMPA receptor-mediated component of the excitatory postsynaptic current [3]. In addition, both in situ hybridization and immunohistochemical staining studies revealed that 5-HT1A receptors, 5-HT7 receptors and the corresponding mRNAs were widely distributed within the primary visual cortex and highly co-localized at the plasma membrane [20,21]. Besides, co-immunoprecipitation studies in mouse brain provided direct evidence that 5-HT1A and 5-HT7 receptors can form heteromers in neurons in vivo [15].
The increase in NMDA receptor-mediated component of mEPSCs by 5-HT and the reversal of NMDA-receptor-mediated long-term depression (LTD) required activation of 5-HT7 receptors, but not 5-HT1A receptors [9,23]. However, the action of 5-HT on glutamatergic synaptic transmission mediated by AMPA receptors in layer II/III pyramidal neurons of the young rat visual cortical slices has not been investigated. Here, we examined the serotonergic regulation of AMPA receptor-mediated mEPSCs (AMPA-mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex. Our results indicated that applications of the 5-HT receptor agonists suppressed glutamatergic synaptic transmission by co-activation of synaptic 5-HT1A receptors and 5-HT7 receptors in layer II/III pyramidal neurons of the young rat visual cortex.
Section snippets
Brain slice preparation
Visual cortex slices were prepared from 13- to 15- day old Sprague-Dawley (SD) rats as previously described [10]. All rats in this study were obtained from the Animal Experiment Centre of our university and housed in a standard animal facility with a 12-h light/12-h dark cycle (light on at 07:00). All animal procedures were performed under guidelines approved by the Laboratory Animal Care Advisory Committee of Xi’an Jiaotong University (NIH publication No. 80-23, revised 1996). Briefly, after
Activation of 5-HT receptors inhibited AMPA receptor-mediated synaptic transmission
we demonstrated that the mEPSCs in the presence of 0.5 μM TTX (Na+ channel blocker), 100 μM picrotoxin (GABAA receptor antagonist), and 1 μM strychnine (glycine receptor antagonist) were comprised of both a fast AMPA receptor-mediated component and a slower NMDA receptor-mediated components (supplementary Fig. 1) [23]. In the same situation as above, exogenous application of 5-HT (1 μM, 10 min) resulted in the inhibition of glutamatergic synaptic transmission (Fig. 1A). As shown in Fig. 1B,
Discussion
Previous literatures have reported that 5-HT caused a reduction of AMPA receptor-mediated currents in the rat nucleus tractus solitarii, hippocampus and prefrontal cortex [1,3]. Consonant with these results, our results showed that exogenous application of 5-HT reduced AMPA receptor-mediated synaptic transmission in the rat visual cortex, indicating a complex pattern of modulation of glutamatergic synaptic transmission and highlighting the role of 5-HT receptors in remodeling of neuronal wiring
Conflict of interest
The authors declare that they have no conflicts of interest to disclose.
Acknowledgements
This study was supported by theNatural Science Basic Research Plan in Shaanxi Province of China (No. 2017JM3035) and the National Natural Science Foundation of China (No. 31000480 and 61431012).
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