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The estrous cycle is caused by the changing concentration of ovarian hormones, particularly 17β-estradiol, a hormone whose effect on excitatory circuits has been extensively reported. However, fewer studies have tried to elucidate how this cycle, or this hormone, affects the plasticity of inhibitory networks and the structure of interneurons. Among these cells, somatostatin-expressing O-LM neurons of the hippocampus are especially interesting. They have a role in the modulation of theta oscillations, and they receive direct input from the entorhinal cortex, which place them in the center of hippocampal function. In this study, we report that the expression of polysialylated form of the neural cell adhesion molecule (PSA-NCAM) in the hippocampus, a molecule involved in the plasticity of somatostatin-expressing interneurons in the adult brain, fluctuated through the different stages of the estrous cycle. Likewise, these stages and the expression of PSA-NCAM affected the density of dendritic spines of O-LM cells. We also describe that 17β-estradiol replacement of adult ovariectomized female mice caused an increase in the perisomatic inhibitory puncta in O-LM interneurons as well as an increase in their axonal bouton density. Interestingly, this treatment also induced a decrease in their dendritic spine density, specifically in O-LM interneurons lacking PSA-NCAM expression. Finally, using an ex vivo real-time assay with entorhinal-hippocampal organotypic cultures, we show that this hormone decreased the dynamics in spinogenesis, altogether highlighting the modulatory effect that 17β-estradiol has on inhibitory circuits., (© 2021 S. Karger AG, Basel.)

Although the precise mechanism of action of antidepressant drugs remains elusive, the neuroplastic hypothesis has gained acceptance during the last two decades. Several studies have shown that treatment with antidepressants such as Fluoxetine is associated with enhanced plasticity in control animals, especially in regions such as the visual cortex, the hippocampus and the medial prefrontal cortex. More recently, the basolateral amygdala has been shown to be affected by Fluoxetine leading to a reopening of critical period-like plasticity in the fear and aggression circuits. One of the key elements triggering this type of brain plasticity are inhibitory networks, especially parvalbumin interneurons. However, recent work on fast-acting antidepressants has shown also an important role for somatostatin interneurons. Here we show that Fluoxetine reorganizes inhibitory circuits through increased expression of the plasticity-related molecule PSA-NCAM which regulates interneuronal structure and connectivity. In addition, we demonstrate that treatment with this antidepressant alters the structure of somatostatin interneurons both at the level of dendritic spines and of axonal en passant boutons. Our findings suggest that new strategies targeting somatostatin interneuron activity might help us to better understand depression and the action of antidepressants., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Diabetes mellitus patients are at increased risk of developing depression, although the neurobiological bases of this comorbidity are not yet fully understood. These patients show CNS alterations, similar to those found in major depression, including changes in the structure and neurotransmission of excitatory neurons. However, although depressive patients and animal models also display alterations in inhibitory networks, little is known about the effects of diabetes on interneurons. Our main objective was to study the impact of diabetes on interneurons of the medial prefrontal cortex (mPFC), one of the regions most affected by major depression. For this purpose we have induced diabetes with high-dose streptozotozin in transgenic mice displaying fluorescent interneurons. These animals showed a depressive-like behavior (increased immobility time in tail suspension test) in parallel with reductions in interneuronal dendritic arborization and in the expression of GAD67, the enzyme that synthetizes the inhibitory neurotransmitter GABA. However, the levels of PSA-NCAM, a plasticity-related molecule exclusively expressed by interneurons in the mPFC, were unaltered in the different regions and layers of this cortical area. Interestingly, diabetic mice also showed increased levels of synaptophysin, a synaptic vesicle protein. These results indicate that the structure and neurotransmission of interneurons is altered in the mPFC of diabetic mice and suggest that these changes may play a key role in the depressive symptoms associated to diabetes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Excitatory neurons undergo dendritic spine remodeling in response to different stimuli. However, there is scarce information about this type of plasticity in interneurons. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is a good candidate to mediate this plasticity as it participates in neuronal remodeling and is expressed by some mature cortical interneurons, which have reduced dendritic arborization, spine density, and synaptic input. To study the connectivity of the dendritic spines of interneurons and the influence of PSA-NCAM on their dynamics, we have analyzed these structures in a subpopulation of fluorescent spiny interneurons in the hippocampus of glutamic acid decarboxylase-enhanced green fluorescent protein transgenic mice. Our results show that these spines receive excitatory synapses. The depletion of PSA in vivo using the enzyme Endo-Neuraminidase-N (Endo-N) increases spine density when analyzed 2 days after, but decreases it 7 days after. The dendritic spine turnover was also analyzed in real time using organotypic hippocampal cultures: 24 h after the addition of EndoN, we observed an increase in the apparition rate of spines. These results indicate that dendritic spines are important structures in the control of the synaptic input of hippocampal interneurons and suggest that PSA-NCAM is relevant in the regulation of their morphology and connectivity., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Novel hypotheses suggest that antidepressants, such as the selective serotonin reuptake inhibitor fluoxetine, induce neuronal structural plasticity, resembling that of the juvenile brain, although the underlying mechanisms of this reopening of the critical periods still remain unclear. However, recent studies suggest that inhibitory networks play an important role in this structural plasticity induced by fluoxetine. For this reason we have analysed the effects of a chronic fluoxetine treatment in the hippocampus and medial prefrontal cortex (mPFC) of transgenic mice displaying eGFP labelled interneurons. We have found an increase in the expression of molecules related to critical period plasticity, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), GAD67/65 and synaptophysin, as well as a reduction in the number of parvalbumin expressing interneurons surrounded by perineuronal nets. We have also described a trend towards decrease in the perisomatic inhibitory puncta on pyramidal neurons in the mPFC and an increase in the density of inhibitory puncta on eGFP interneurons. Finally, we have found that chronic fluoxetine treatment affects the structure of interneurons in the mPFC, increasing their dendritic spine density. The present study provides evidence indicating that fluoxetine promotes structural changes in the inhibitory neurons of the adult cerebral cortex, probably through alterations in plasticity-related molecules of neurons or the extracellular matrix surrounding them, which are present in interneurons and are known to be crucial for the development of the critical periods of plasticity in the juvenile brain.

N-methyl-D-aspartate receptors (NMDARs) are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP) in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing interneurons. Twenty-four hours after the injection, the density of spines did not vary, but we found a significant increase in the density of their en passant boutons (EPB). We have also used entorhinohippocampal organotypic cultures to study these interneurons in real-time. There was a rapid decrease in the apparition rate of spines after MK-801 administration, which persisted for 24 h and returned to basal levels afterwards. A similar reversible decrease was detected in spine density. Our results show that both spines and axons of interneurons can undergo remodeling and highlight NMDARs as regulators of this plasticity. These results are specially relevant given the importance of all these players on hippocampal physiology and the etiopathology of certain psychiatric disorders. [ABSTRACT FROM AUTHOR]

Adverse experiences during infancy and adolescence have an important and enduring effect on the brain and are predisposing factors for mental disorders, particularly major depression. This impact is particularly notable in regions with protracted development, such as the prefrontal cortex. The inhibitory neurons of this cortical region are altered by peripubertal stress (PPS), particularly in female mice. In this study we have explored whether the inhibitory circuits of the thalamus are impacted by PPS in male and female mice. This diencephalic structure, as the prefrontal cortex, also completes its development during postnatal life and is affected by adverse experiences. The long-term changes induced by PPS were exclusively found in adult female mice. We have found that PPS increases depressive-like behavior and induces changes in parvalbumin-expressing (PV+) cells of the thalamic reticular nucleus (TRN). We observed reductions in the volume of the TRN, together with those of parameters related to structures/molecules that regulate the plasticity and connectivity of PV+ cells: perineuronal nets, matricellular structures surrounding PV+ neurons, and the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). The expression of the GluN1, but not of GluN2C, NMDA receptor subunit was augmented in the TRN after PPS. An increase in the fluorescence intensity of PV+ puncta was also observed in the synaptic output of TRN neurons in the lateral posterior thalamic nucleus. These results demonstrate that the inhibitory circuits of the thalamus, as those of the prefrontal cortex, are vulnerable to the effects of aversive experiences during early life, particularly in females. This vulnerability is probably related to the protracted development of the TRN and might contribute to the development of psychiatric disorders. [ABSTRACT FROM AUTHOR]