scholarly journals Chronic Administration of 13-cis-retinoic Acid Induces Depression-Like Behavior by Altering the Activity of Dentate Granule Cells

2021 ◽  
Author(s):  
Xiao-Hong Su ◽  
Wei-Peng Li ◽  
Yi-Jie Wang ◽  
Jia Liu ◽  
Jun-Yu Liu ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Neural Activity ◽  
Clinical Case ◽  
Granule Cells ◽  
Case Reports ◽  
Chronic Administration ◽  
Intrinsic Excitability ◽  
Dentate Granule Cells ◽  
Whole Cell Patch Clamp ◽  
Cellular Target

AbstractDepression is a common but serious mental disorder and can be caused by the side effects of medications. Evidence from abundant clinical case reports and experimental animal models has revealed the association between the classic anti-acne drug 13-cis-retinoic acid (13-cis-RA) and depressive symptoms. However, direct experimental evidence of this mechanism and information on appropriate therapeutic rescue strategies are lacking. Herein, our data revealed that chronic administration of 13-cis-RA to adolescent mice induced depression-like behavior but not anxiety-like behavior. We next demonstrated that chronic 13-cis-RA application increased neural activity in the dentate gyrus (DG) using c-Fos immunostaining, which may be critically involved in some aspects of depression-like behavior. Therefore, we assessed electrophysiological functions by obtaining whole-cell patch-clamp recordings of dentate granule cells (DGCs), which revealed that chronic 13-cis-RA treatment shifted the excitatory-inhibitory balance toward excitation and increased intrinsic excitability. Furthermore, a pharmacogenetic approach was performed to repeatedly silence DGCs, and this manipulation could rescue depression-like behavior in chronically 13-cis-RA-treated mice, suggesting DGCs as a potential cellular target for the direct alleviation of 13-cis-RA-induced depression.

scholarly journals All-trans retinoic acid induces synaptopodin-dependent metaplasticity in mouse dentate granule cells

2021 ◽  
Author(s):  
Maximilian Lenz ◽  
Amelie Eichler ◽  
Pia Kruse ◽  
Julia Muellerleile ◽  
Thomas Deller ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Brain Region ◽  
Granule Cells ◽  
Atra Treatment ◽  
Dentate Granule Cells ◽  
Inhibitory Neurotransmission ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

The vitamin A derivative all-trans retinoic acid (atRA) is a key mediator of synaptic plasticity. Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. However, it remains unclear how atRA mediates brain region-specific effects on synaptic transmission and plasticity. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult male C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata. In contrast to what has been reported in other brain regions, no major changes in synaptic transmission were observed in the ventral and dorsal hippocampus 6 hours after atRA administration. Likewise, no evidence for changes in the intrinsic properties of hippocampal dentate granule cells was obtained in the atRA-treated group. Moreover, hippocampal transcriptome analysis revealed no essential changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, i.e., for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic transmission. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in synaptopodin-deficient mice, thus extending our previous results on the relevance of synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates synaptopodin-dependent metaplasticity in mouse dentate granule cells.

scholarly journals TWIK-1 contributes to the intrinsic excitability of dentate granule cells in mouse hippocampus

2014 ◽  
Vol 7 (1) ◽  
Author(s):  
Oleg Yarishkin ◽  
Da Yong Lee ◽  
Eunju Kim ◽  
Chang-Hoon Cho ◽  
Jae Hyouk Choi ◽  
...  
Keyword(s):  
Granule Cells ◽  
Intrinsic Excitability ◽  
Dentate Granule Cells ◽  
Mouse Hippocampus

scholarly journals All-trans retinoic acid induces synaptopodin-dependent metaplasticity in mouse dentate granule cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Maximilian Lenz ◽  
Amelie Eichler ◽  
Pia Kruse ◽  
Julia Muellerleile ◽  
Thomas Deller ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Brain Region ◽  
Granule Cells ◽  
Long Term Potentiation ◽  
Atra Treatment ◽  
Dentate Granule Cells ◽  
Inhibitory Neurotransmission ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Previously we showed that the vitamin A metabolite all-trans retinoic acid (atRA) induces synaptic plasticity in acute brain slices prepared from the mouse and human neocortex (Lenz et al., 2021). Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata—a brain region implicated in memory acquisition. No major changes in synaptic transmission were observed in the ventral hippocampus while a significant increase in both spontaneous excitatory postsynaptic current frequencies and synapse numbers were evident in the dorsal hippocampus 6 hr after atRA administration. The intrinsic properties of hippocampal dentate granule cells were not significantly different and hippocampal transcriptome analysis revealed no essential neuronal changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, that is, for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic strength. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in synaptopodin-deficient mice, therefore, extending our previous results regarding the relevance of synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates synaptopodin-dependent metaplasticity in mouse dentate granule cells.

scholarly journals Heterogeneities in intrinsic excitability and frequency-dependent response properties of granule cells across the blades of the rat dentate gyrus

2020 ◽  
Vol 123 (2) ◽  
pp. 755-772 ◽  
Author(s):  
Poonam Mishra ◽  
Rishikesh Narayanan
Keyword(s):  
Patch Clamp ◽  
Action Potential ◽  
Dentate Gyrus ◽  
Temporal Summation ◽  
Granule Cells ◽  
Intrinsic Excitability ◽  
Frequency Dependent ◽  
Response Properties ◽  
Whole Cell Patch Clamp ◽  
Afferent Information

The dentate gyrus (DG), the input gate to the hippocampus proper, is anatomically segregated into three different sectors, namely, the suprapyramidal blade, the crest region, and the infrapyramidal blade. Although there are well-established differences between these sectors in terms of neuronal morphology, connectivity patterns, and activity levels, differences in electrophysiological properties of granule cells within these sectors have remained unexplored. Here, employing somatic whole cell patch-clamp recordings from the rat DG, we demonstrate that granule cells in these sectors manifest considerable heterogeneities in their intrinsic excitability, temporal summation, action potential characteristics, and frequency-dependent response properties. Across sectors, these neurons showed positive temporal summation of their responses to inputs mimicking excitatory postsynaptic currents and showed little to no sag in their voltage responses to pulse currents. Consistently, the impedance amplitude profile manifested low-pass characteristics and the impedance phase profile lacked positive phase values at all measured frequencies and voltages and for all sectors. Granule cells in all sectors exhibited class I excitability, with broadly linear firing rate profiles, and granule cells in the crest region fired significantly fewer action potentials compared with those in the infrapyramidal blade. Finally, we found weak pairwise correlations across the 18 different measurements obtained individually from each of the three sectors, providing evidence that these measurements are indeed reporting distinct aspects of neuronal physiology. Together, our analyses show that granule cells act as integrators of afferent information and emphasize the need to account for the considerable physiological heterogeneities in assessing their roles in information encoding and processing. NEW & NOTEWORTHY We employed whole cell patch-clamp recordings from granule cells in the three subregions of the rat dentate gyrus to demonstrate considerable heterogeneities in their intrinsic excitability, temporal summation, action potential characteristics, and frequency-dependent response properties. Across sectors, granule cells did not express membrane potential resonance, and their impedance profiles lacked inductive phase leads at all measured frequencies. Our analyses also show that granule cells manifest class I excitability characteristics, categorizing them as integrators of afferent information.

scholarly journals Mature dentate granule cells show different intrinsic properties depending on the behavioral context of their activation

2018 ◽  
Author(s):  
Angélique Peret ◽  
Claire Pléau ◽  
Edouard Pearlstein ◽  
Thomas Scalfati ◽  
Geoffrey Marti ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Home Cage ◽  
Granule Cells ◽  
Ex Vivo ◽  
Spatial Navigation ◽  
Intrinsic Excitability ◽  
Intrinsic Properties ◽  
Behavioral Context ◽  
Dentate Granule Cells ◽  
Neural Signature

AbstractThe dentate gyrus (DG) plays a crucial role in learning, memory and spatial navigation. Only a small fraction of mature dentate granule cells (mDGCs) is active during behavior, while the large majority remains silent. To date, the properties of this active subset of neurons remain poorly investigated. Using fosGFP transgenic mice, we show ex vivo that activated mDGCs, from mice maintained in their home cage, exhibit a marked lower intrinsic excitability compared to the non-activated cells. Remarkably, activated mDGCs, from mice trained in a virtual environment, are more excitable than those from mice maintained in their home cage. Therefore, we show that activated mDGCs display different intrinsic properties and excitable states depending on the context of their activation. We propose that these properties could constitute a neural signature of cell assemblies recruited in different behavioral contexts.

Changes in mIPSCs and sIPSCs After Kainate Treatment: Evidence for Loss of Inhibitory Input to Dentate Granule Cells and Possible Compensatory Responses

2005 ◽  
Vol 94 (2) ◽  
pp. 952-960 ◽  
Author(s):  
Li-Rong Shao ◽  
F. Edward Dudek
Keyword(s):  
Status Epilepticus ◽  
Granule Cells ◽  
Mean Amplitude ◽  
Inhibitory Input ◽  
Similar Reduction ◽  
Dentate Granule Cells ◽  
Whole Cell Patch Clamp ◽  
The Mean ◽  
Inhibitory Synaptic Input

How inhibition is altered after status epilepticus and the role of inhibition during epileptogenesis remain unsettled issues. The present study examined acute (4–7 days) and chronic (>3 mo) changes of GABAA receptor-mediated inhibitory synaptic input to dentate granule cells after kainate-induced status epilepticus. Whole cell patch-clamp techniques were used to record spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in the presence of 6,7-dinitroquinoxaline-2,3-dione and dl-2-amino-5-phosphonopentanoic acid to block glutamatergic excitatory synaptic transmission. In both groups, mean sIPSC frequency of dentate granule cells from the saline- and kainate-treated rats was not significantly different. However, mIPSC frequency from the kainate-treated rats of both groups was ∼30% lower than that of the respective saline controls. The mean amplitude of sIPSCs and mIPSCs from kainate-treated rats was not reduced in either the acute or chronic groups. The mean 10–90% rise time of IPSCs was not altered in kainate-treated rats, but the decay time constant was slightly longer than in controls, and the charge transfer 4–7 days after kainate treatment was significantly larger. The similar reduction of mIPSC frequency (i.e., ∼30%) in the two groups of kainate-treated rats suggests a decreased inhibitory input to dentate granule cells (presumably due to a partial loss of inhibitory interneurons that innervate them) without recovery during epileptogenesis. The lack of effect on sIPSC frequency and the decreased mIPSC frequency in both groups suggests a possible compensatory increase in firing rate of interneurons, which may involve a hypothetical reduction of inhibitory input to the remaining interneurons.

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