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Remodeling and Tenacity of Inhibitory Synapses: Relationships with Network Activity and Neighboring Excitatory Synapses  [PDF]
Anna Rubinski?,Noam E. Ziv
PLOS Computational Biology , 2015, DOI: 10.1371/journal.pcbi.1004632
Abstract: Glutamatergic synapse size remodeling is governed not only by specific activity forms but also by apparently stochastic processes with well-defined statistics. These spontaneous remodeling processes can give rise to skewed and stable synaptic size distributions, underlie scaling of these distributions and drive changes in glutamatergic synapse size “configurations”. Where inhibitory synapses are concerned, however, little is known on spontaneous remodeling dynamics, their statistics, their activity dependence or their long-term consequences. Here we followed individual inhibitory synapses for days, and analyzed their size remodeling dynamics within the statistical framework previously developed for glutamatergic synapses. Similar to glutamatergic synapses, size distributions of inhibitory synapses were skewed and stable; at the same time, however, sizes of individual synapses changed considerably, leading to gradual changes in synaptic size configurations. The suppression of network activity only transiently affected spontaneous remodeling dynamics, did not affect synaptic size configuration change rates and was not followed by the scaling of inhibitory synapse size distributions. Comparisons with glutamatergic synapses within the same dendrites revealed a degree of coupling between nearby inhibitory and excitatory synapse remodeling, but also revealed that inhibitory synapse size configurations changed at considerably slower rates than those of their glutamatergic neighbors. These findings point to quantitative differences in spontaneous remodeling dynamics of inhibitory and excitatory synapses but also reveal deep qualitative similarities in the processes that control their sizes and govern their remodeling dynamics.
Neuroligin 2 Is Expressed in Synapses Established by Cholinergic Cells in the Mouse Brain  [PDF]
Virág T. Takács, Tamás F. Freund, Gábor Nyiri
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072450
Abstract: Neuroligin 2 is a postsynaptic protein that plays a critical role in the maturation and proper function of GABAergic synapses. Previous studies demonstrated that deletion of neuroligin 2 impaired GABAergic synaptic transmission, whereas its overexpression caused increased inhibition, which suggest that its presence strongly influences synaptic function. Interestingly, the overexpressing transgenic mouse line showed increased anxiety-like behavior and other behavioral phenotypes, not easily explained by an otherwise strengthened GABAergic transmission. This suggested that other, non-GABAergic synapses may also express neuroligin 2. Here, we tested the presence of neuroligin 2 at synapses established by cholinergic neurons in the mouse brain using serial electron microscopic sections double labeled for neuroligin 2 and choline acetyltransferase. We found that besides GABAergic synapses, neuroligin 2 is also present in the postsynaptic membrane of cholinergic synapses in all investigated brain areas (including dorsal hippocampus, somatosensory and medial prefrontal cortices, caudate putamen, basolateral amygdala, centrolateral thalamic nucleus, medial septum, vertical- and horizontal limbs of the diagonal band of Broca, substantia innominata and ventral pallidum). In the hippocampus, the density of neuroligin 2 labeling was similar in GABAergic and cholinergic synapses. Moreover, several cholinergic contact sites that were strongly labeled with neuroligin 2 did not resemble typical synapses, suggesting that cholinergic axons form more synaptic connections than it was recognized previously. We showed that cholinergic cells themselves also express neuroligin 2 in a subset of their input synapses. These data indicate that mutations in human neuroligin 2 gene and genetic manipulations of neuroligin 2 levels in rodents will potentially cause alterations in the cholinergic system as well, which may also have a profound effect on the functional properties of brain circuits and behavior.
Ultrastructural characterization of GABAergic and excitatory synapses in the inferior colliculus  [PDF]
Kyle T. Nakamoto,Jeffrey G. Mellott,Colleen S. Sowick,Brett R. Schofield
Frontiers in Neuroanatomy , 2014, DOI: 10.3389/fnana.2014.00108
Abstract: In the inferior colliculus (IC) cells integrate inhibitory input from the brainstem and excitatory input from both the brainstem and auditory cortex. In order to understand how these inputs are integrated by IC cells identification of their synaptic arrangements is required. We used electron microscopy to characterize GABAergic synapses in the dorsal cortex, central nucleus, and lateral cortex of the IC (ICd, ICc, and IClc) of guinea pigs. Throughout the IC, GABAergic synapses are characterized by pleomorphic vesicles and symmetric junctions. Comparisons of GABAergic synapses with excitatory synapses revealed differences (in some IC subdivisions) between the distributions of these synapse types onto IC cells. For excitatory cells in the IClc and ICd GABAergic synapses are biased toward the somas and large dendrites, whereas the excitatory boutons are biased toward spines and small dendrites. This arrangement could allow for strong inhibitory gating of excitatory inputs. Such differences in synaptic distributions were not observed in the ICc, where the two classes of bouton have similar distributions along the dendrites of excitatory cells. Interactions between excitatory and GABAergic inputs on the dendrites of excitatory ICc cells may be more restricted (i.e., reflecting local dendritic processing) than in the other IC subdivisions. Comparisons across IC subdivisions revealed evidence for two classes of GABAergic boutons, a small GABAergic (SG) class that is present throughout the IC and a large GABAergic (LG) class that is almost completely restricted to the ICc. In the ICc, LG, and SG boutons differ in their targets. SG boutons contact excitatory dendritic shafts most often, but also contact excitatory spines and somas (excitatory and GABAergic). LG synapses make comparatively fewer contacts on excitatory shafts, and make comparatively more contacts on excitatory spines and on somas (excitatory and GABAergic). LG boutons likely have a lemniscal origin.
Neuroligin-1 Overexpression in Newborn Granule Cells In Vivo  [PDF]
Eric Schnell, AeSoon L. Bensen, Eric K. Washburn, Gary L. Westbrook
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048045
Abstract: Adult-born dentate granule cells integrate into the hippocampal network, extend neurites and form synapses in otherwise mature tissue. Excitatory and inhibitory inputs innervate these new granule cells in a stereotyped, temporally segregated manner, which presents a unique opportunity to study synapse development in the adult brain. To examine the role of neuroligins as synapse-inducing molecules in vivo, we infected dividing neural precursors in adult mice with a retroviral construct that increased neuroligin-1 levels during granule cell differentiation. By 21 days post-mitosis, exogenous neuroligin-1 was expressed at the tips of dendritic spines and increased the number of dendritic spines. Neuroligin-1-overexpressing cells showed a selective increase in functional excitatory synapses and connection multiplicity by single afferent fibers, as well as an increase in the synaptic AMPA/NMDA receptor ratio. In contrast to its synapse-inducing ability in vitro, neuroligin-1 overexpression did not induce precocious synapse formation in adult-born neurons. However, the dendrites of neuroligin-1-overexpressing cells did have more thin protrusions during an early period of dendritic outgrowth, suggesting enhanced filopodium formation or stabilization. Our results indicate that neuroligin-1 expression selectively increases the degree, but not the onset, of excitatory synapse formation in adult-born neurons.
N-Cofilin Can Compensate for the Loss of ADF in Excitatory Synapses  [PDF]
Andreas G?rlich, Michael Wolf, Anika-Maria Zimmermann, Christine B. Gurniak, Mumna Al Banchaabouchi, Marco Sassoè-Pognetto, Walter Witke, Eckhard Friauf, Marco B. Rust
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026789
Abstract: Actin plays important roles in a number of synaptic processes, including synaptic vesicle organization and exocytosis, mobility of postsynaptic receptors, and synaptic plasticity. However, little is known about the mechanisms that control actin at synapses. Actin dynamics crucially depend on LIM kinase 1 (LIMK1) that controls the activity of the actin depolymerizing proteins of the ADF/cofilin family. While analyses of mouse mutants revealed the importance of LIMK1 for both pre- and postsynaptic mechanisms, the ADF/cofilin family member n-cofilin appears to be relevant merely for postsynaptic plasticity, and not for presynaptic physiology. By means of immunogold electron microscopy and immunocytochemistry, we here demonstrate the presence of ADF (actin depolymerizing factor), a close homolog of n-cofilin, in excitatory synapses, where it is particularly enriched in presynaptic terminals. Surprisingly, genetic ablation of ADF in mice had no adverse effects on synapse structure or density as assessed by electron microscopy and by the morphological analysis of Golgi-stained hippocampal pyramidal cells. Moreover, a series of electrophysiological recordings in acute hippocampal slices revealed that presynaptic recruitment and exocytosis of synaptic vesicles as well as postsynaptic plasticity were unchanged in ADF mutant mice. The lack of synaptic defects may be explained by the elevated n-cofilin levels observed in synaptic structures of ADF mutants. Indeed, synaptic actin regulation was impaired in compound mutants lacking both ADF and n-cofilin, but not in ADF single mutants. From our results we conclude that n-cofilin can compensate for the loss of ADF in excitatory synapses. Further, our data suggest that ADF and n-cofilin cooperate in controlling synaptic actin content.
Regulation of Excitatory Synapses and Fearful Memories by Stress Hormones  [PDF]
Harm J. Krugers
Frontiers in Behavioral Neuroscience , 2011, DOI: 10.3389/fnbeh.2011.00062
Abstract: Memories for emotionally arousing and fearful events are generally well retained. From the evolutionary point of view this is a highly adaptive behavioral response aimed to remember relevant information. However, fearful memories can also be inappropriately and vividly (re)expressed, such as in posttraumatic stress disorder. The memory formation of emotionally arousing events is largely modulated by hormones, peptides, and neurotransmitters which are released during and after exposure to these conditions. One of the core reactions in response to a stressful situation is the rapid activation of the autonomic nervous system, which results in the release of norepinephrine in the brain. In addition, stressful events stimulate the hypothalamus–pituitary–adrenal axis which slowly increases the release of glucocorticoid hormones from the adrenal glands. Here we will review how glucocorticoids and norepinephrine regulate the formation of fearful memories in rodents and humans and how these hormones can facilitate the storage of information by regulating excitatory synapses.
Spatial Distribution of Excitatory Synapses on the Dendrites of Ganglion Cells in the Mouse Retina  [PDF]
Yin-Peng Chen, Chuan-Chin Chiao
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086159
Abstract: Excitatory glutamatergic inputs from bipolar cells affect the physiological properties of ganglion cells in the mammalian retina. The spatial distribution of these excitatory synapses on the dendrites of retinal ganglion cells thus may shape their distinct functions. To visualize the spatial pattern of excitatory glutamatergic input into the ganglion cells in the mouse retina, particle-mediated gene transfer of plasmids expressing postsynaptic density 95-green fluorescent fusion protein (PSD95-GFP) was used to label the excitatory synapses. Despite wide variation in the size and morphology of the retinal ganglion cells, the expression of PSD95 puncta was found to follow two general rules. Firstly, the PSD95 puncta are regularly spaced, at 1–2 μm intervals, along the dendrites, whereby the presence of an excitatory synapse creates an exclusion zone that rules out the presence of other glutamatergic synaptic inputs. Secondly, the spatial distribution of PSD95 puncta on the dendrites of diverse retinal ganglion cells are similar in that the number of excitatory synapses appears to be less on primary dendrites and to increase to a plateau on higher branch order dendrites. These observations suggest that synaptogenesis is spatially regulated along the dendritic segments and that the number of synaptic contacts is relatively constant beyond the primary dendrites. Interestingly, we also found that the linear puncta density is slightly higher in large cells than in small cells. This may suggest that retinal ganglion cells with a large dendritic field tend to show an increased connectivity of excitatory synapses that makes up for their reduced dendrite density. Mapping the spatial distribution pattern of the excitatory synapses on retinal ganglion cells thus provides explicit structural information that is essential for our understanding of how excitatory glutamatergic inputs shape neuronal responses.
New players tip the scales in the balance between excitatory and inhibitory synapses
Joshua N Levinson, Alaa El-Husseini
Molecular Pain , 2005, DOI: 10.1186/1744-8069-1-12
Abstract: In the brain, excitatory and inhibitory synaptic transmission is mainly mediated by two neurotransmitters: glutamate which is released at excitatory glutamatergic synaptic contacts, and γ-amino butyric acid (GABA) which is released at inhibitory GABAergic synapses. Neural information processing is believed to be mediated by integration of excitatory and inhibitory synaptic inputs [1-3]. Therefore, precise controls must exist to maintain an appropriate number of one type of synaptic input relative to the other. This process is thought to be governed by homeostatic feedback mechanisms, however factors involved remain elusive [4,5]. Impressive work carried out in recent years has begun to address the roles of molecules involved in synapse formation. A theme that has emerged from these studies is that glutamatergic and GABAergic synapses consist of complex, yet distinct networks of proteins on the postsynaptic side. The major challenge in this field now is to understand how this molecular machinery is involved in synapse formation and specificity.The discovery of a protein complex that regulates postsynaptic glutamate receptor clustering and the formation of dendritic spines has revealed some of the mechanisms involved in excitatory synapse development. Two main groups of key regulators of excitatory synapse formation have been identified, namely postsynaptic scaffolding proteins and cell adhesion molecules (CAMs). In the first group, several proteins including members of the PSD-95 family, shank, and homer have been shown to promote excitatory synapse maturation (reviewed in [6]). Much work has focused on postsynaptic density protein-95 (PSD-95), one of the most abundant proteins in the PSD [6]. PSD-95 clustering at synapses occurs early in development, prior to other postsynaptic proteins [7], and discs large, a Drosophila homolog of PSD-95, is required for normal neuromuscular junction development in larva [8]. In addition, PSD-95 enhances AMPA-type glutamate recepto
Transitions in Oscillatory Dynamics of Two Connected Neurons with Excitatory Synapses  [PDF]
Yasser Roudi,Shahin Rouhani
Quantitative Biology , 2002,
Abstract: It is shown that long term behavior of two connected Integrate- and- Fire neurons with excitatory synapses is determined by some fixed-points. In the case of equal synaptic weights four different dynamic phases are found. Between these phases there is a specific phase with a global attractor fixed-point, which is of interest from different viewpoints. Simulations support our analytic work. When synaptic weights are equal we observe no synchronization but with different weight we do observe an almost synchronous state. Simulations show that when there is only one non-trivial fixed-point the period of oscillations is stable against small changes in synaptic weights
Preserved Morphology and Physiology of Excitatory Synapses in Profilin1-Deficient Mice  [PDF]
Andreas G?rlich, Anika-Maria Zimmermann, Doreen Schober, Ralph T. B?ttcher, Marco Sassoè-Pognetto, Eckhard Friauf, Walter Witke, Marco B. Rust
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030068
Abstract: Profilins are important regulators of actin dynamics and have been implicated in activity-dependent morphological changes of dendritic spines and synaptic plasticity. Recently, defective presynaptic excitability and neurotransmitter release of glutamatergic synapses were described for profilin2-deficient mice. Both dendritic spine morphology and synaptic plasticity were fully preserved in these mutants, bringing forward the hypothesis that profilin1 is mainly involved in postsynaptic mechanisms, complementary to the presynaptic role of profilin2. To test the hypothesis and to elucidate the synaptic function of profilin1, we here specifically deleted profilin1 in neurons of the adult forebrain by using conditional knockout mice on a CaMKII-cre-expressing background. Analysis of Golgi-stained hippocampal pyramidal cells and electron micrographs from the CA1 stratum radiatum revealed normal synapse density, spine morphology, and synapse ultrastructure in the absence of profilin1. Moreover, electrophysiological recordings showed that basal synaptic transmission, presynaptic physiology, as well as postsynaptic plasticity were unchanged in profilin1 mutants. Hence, loss of profilin1 had no adverse effects on the morphology and function of excitatory synapses. Our data are in agreement with two different scenarios: i) profilins are not relevant for actin regulation in postsynaptic structures, activity-dependent morphological changes of dendritic spines, and synaptic plasticity or ii) profilin1 and profilin2 have overlapping functions particularly in the postsynaptic compartment. Future analysis of double mutant mice will ultimately unravel whether profilins are relevant for dendritic spine morphology and synaptic plasticity.
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