Lithium causes differential effects on postsynaptic stability in normal and denervated neuromuscular synapses.

Lithium chloride has been widely used as a therapeutic mood stabilizer. Although cumulative evidence suggests that lithium plays modulatory effects on postsynaptic receptors, the underlying mechanism by which lithium regulates synaptic transmission has not been fully elucidated. In this work, by using the advantageous neuromuscular synapse, we evaluated the effect of lithium on the stability of postsynaptic nicotinic acetylcholine receptors (nAChRs) in vivo. We found that in normally innervated neuromuscular synapses, lithium chloride significantly decreased the turnover of nAChRs by reducing their internalization. A similar response was observed in CHO-K1/A5 cells expressing the adult muscle-type nAChRs. Strikingly, in denervated neuromuscular synapses, lithium led to enhanced nAChR turnover and density by increasing the incorporation of new nAChRs. Lithium also potentiated the formation of unstable nAChR clusters in non-synaptic regions of denervated muscle fibres. We found that denervation-dependent re-expression of the foetal nAChR γ-subunit was not altered by lithium. However, while denervation inhibits the distribution of ß-catenin within endplates, lithium-treated fibres retain ß-catenin staining in specific foci of the synaptic region. Collectively, our data reveal that lithium treatment differentially affects the stability of postsynaptic receptors in normal and denervated neuromuscular synapses in vivo, thus providing novel insights into the regulatory effects of lithium on synaptic organization and extending its potential therapeutic use in conditions affecting the peripheral nervous system.

Small-worldness favours network inference in synthetic neural networks.

A main goal in the analysis of a complex system is to infer its underlying network structure from time-series observations of its behaviour. The inference process is often done by using bi-variate similarity measures, such as the cross-correlation (CC) or mutual information (MI), however, the main factors favouring or hindering its success are still puzzling. Here, we use synthetic neuron models in order to reveal the main topological properties that frustrate or facilitate inferring the underlying network from CC measurements. Specifically, we use pulse-coupled Izhikevich neurons connected as in the Caenorhabditis elegans neural networks as well as in networks with similar randomness and small-worldness. We analyse the effectiveness and robustness of the inference process under different observations and collective dynamics, contrasting the results obtained from using membrane potentials and inter-spike interval time-series. We find that overall, small-worldness favours network inference and degree heterogeneity hinders it. In particular, success rates in C. elegans networks - that combine small-world properties with degree heterogeneity - are closer to success rates in Erdös-Rényi network models rather than those in Watts-Strogatz network models. These results are relevant to understand better the relationship between topological properties and function in different neural networks.

Functional comparison of corticostriatal and thalamostriatal postsynaptic responses in striatal neurons of the mouse.

Synaptic inputs from cortex and thalamus were compared in electrophysiologically defined striatal cell classes: direct and indirect pathways' striatal projection neurons (dSPNs and iSPNs), fast-spiking interneurons (FS), cholinergic interneurons (ChINs), and low-threshold spiking-like (LTS-like) interneurons. Our purpose was to observe whether stimulus from cortex or thalamus had equivalent synaptic strength to evoke prolonged suprathreshold synaptic responses in these neuron classes. Subthreshold responses showed that inputs from either source functionally mix up in their dendrites at similar electrotonic distances from their somata. Passive and active properties of striatal neuron classes were consistent with the previous studies. Cre-dependent adeno-associated viruses containing Td-Tomato or eYFP fluorescent proteins were used to identify target cells. Transfections with ChR2-eYFP driven by the promoters CamKII or EF1.DIO in intralaminar thalamic nuclei using Vglut-2-Cre mice, or CAMKII in the motor cortex were used to stimulate cortical or thalamic afferents optogenetically. Both field stimuli in the cortex or photostimulation of ChR2-YFP cortical fibers evoked similar prolonged suprathreshold responses in SPNs. Photostimulation of ChR2-YFP thalamic afferents also evoked suprathreshold responses. Differences previously described between responses of dSPNs and iSPNs were observed in both cases. Prolonged suprathreshold responses could also be evoked from both sources onto all other neuron classes studied. However, to evoke thalamostriatal suprathreshold responses, afferents from more than one thalamic nucleus had to be stimulated. In conclusion, both thalamus and cortex are capable to generate suprathreshold responses converging on diverse striatal cell classes. Postsynaptic properties appear to shape these responses.

Electroencephalographic Indicators in Default Mode, Habituation, and Visual-motor Association in Female College Students.

BACKGROUND: Oscillations, action, and postsynaptic potentials in glial-neuronal ensembles integrate the spectral power (SP) of electroencephalographic (EEG). Our objective is to propose SP indicators of healthy brains (control groups) based on the default mode and their modifications by habituation and visual-motor association (VM-asso), to support diagnostic and rehabilitation processes. However, important differences seem to exist between men and women. Therefore, we aim to analyze EEG characteristics in a female sample. SUBJECTS AND METHODS: In the current study, EEG was recorded at rest with closed eyes before and during repeated photostimulations (RPh) and before (pre) and during association of RPh with switch pressing (VM-asso) in 70 female adults. EEG was analyzed using UAM/INR software, which removes artifacts, identifies corresponding signals, selects 20 samples (2-s) from each condition, applies Welch's periodogram to calculate and average the absolute power (AP; AAPs) of áµ¹, θ, α, and ß, before and during learning, and emits data to a spreadsheet. Differences in each condition were evaluated using non-parametric tests. RESULTS: The AAPs were different; in habituation, áµ¹ and θ increased significantly in fronto-frontal (FF) and frontocentral and decreased in the other leads. During association, they increased in FF and decreased in the other three regions. α AAP decreased in all leads except in FF during habituation, and the decrement was lower in the association. ß AAP increased in all leads during both learning conditions. CONCLUSION: The SP and the topographic distribution are descriptive parameters of habituation and VM-asso; we propose them as EEG indicators.

Mechanisms regulating dendritic arbor patterning.

The nervous system is populated by diverse types of neurons, each of which has dendritic trees with strikingly different morphologies. These neuron-specific morphologies determine how dendritic trees integrate thousands of synaptic inputs to generate different firing properties. To ensure proper neuronal function and connectivity, it is necessary that dendrite patterns are precisely controlled and coordinated with synaptic activity. Here, we summarize the molecular and cellular mechanisms that regulate the formation of cell type-specific dendrite patterns during development. We focus on different aspects of vertebrate dendrite patterning that are particularly important in determining the neuronal function; such as the shape, branching, orientation and size of the arbors as well as the development of dendritic spine protrusions that receive excitatory inputs and compartmentalize postsynaptic responses. Additionally, we briefly comment on the implications of aberrant dendritic morphology for nervous system disease.

Painful Cervical Facet Joint Injury Is Accompanied by Changes in the Number of Excitatory and Inhibitory Synapses in the Superficial Dorsal Horn That Differentially Relate to Local Tissue Injury Severity.

STUDY DESIGN: Immunohistochemistry labeled pre- and postsynaptic structural markers to quantify excitatory and inhibitory synapses in the spinal superficial dorsal horn at 14 days after painful facet joint injury in the rat. OBJECTIVE: The objective of this study was to investigate the relationship between pain and synapse density in the spinal cord after facet injury. SUMMARY OF BACKGROUND DATA: Neck pain is a major contributor to disability and often becomes chronic. The cervical facet joints are susceptible to loading-induced painful injury, initiating spinal central sensitization responses. Although excitatory synapse plasticity has been reported in the superficial dorsal horn early after painful facet injury, whether excitatory and/or inhibitory synapse density is altered at a time when pain is maintained is unknown. METHODS: Rats underwent either a painful C6/C7 facet joint distraction or sham surgery. Mechanical hyperalgesia was measured and immunohistochemistry techniques for synapse quantification were used to quantify excitatory and inhibitory synapse densities in the superficial dorsal horn at day 14. Logarithmic correlation analyses evaluated whether the severity of facet injury correlated with either behavioral or synaptic outcomes. RESULTS: Facet joint injury induces pain that is sustained until day 14 (P <0.001) and both significantly greater excitatory synapse density (P = 0.042) and lower inhibitory synapse density (P = 0.0029) in the superficial dorsal horn at day 14. Injury severity is significantly correlated with pain at days 1 (P = 0.0011) and 14 (P = 0.0002), but only with inhibitory, not excitatory, synapse density (P = 0.0025) at day 14. CONCLUSION: This study demonstrates a role for structural plasticity in both excitatory and inhibitory synapses in the maintenance of facet-mediated joint pain, and that altered inhibitory, but not excitatory, synapse density correlates to the severity of painful joint injury. Understanding the functional consequences of this spinal structural plasticity is critical to elucidate mechanisms of chronic joint pain. LEVEL OF EVIDENCE: N /A.

Auditory Stimuli Coding by Postsynaptic Potential and Local Field Potential Features.

The relation between physical stimuli and neurophysiological responses, such as action potentials (spikes) and Local Field Potentials (LFP), has recently been experimented in order to explain how neurons encode auditory information. However, none of these experiments presented analyses with postsynaptic potentials (PSPs). In the present study, we have estimated information values between auditory stimuli and amplitudes/latencies of PSPs and LFPs in anesthetized rats in vivo. To obtain these values, a new method of information estimation was used. This method produced more accurate estimates than those obtained by using the traditional binning method; a fact that was corroborated by simulated data. The traditional binning method could not certainly impart such accuracy even when adjusted by quadratic extrapolation. We found that the information obtained from LFP amplitude variation was significantly greater than the information obtained from PSP amplitude variation. This confirms the fact that LFP reflects the action of many PSPs. Results have shown that the auditory cortex codes more information of stimuli frequency with slow oscillations in groups of neurons than it does with slow oscillations in neurons separately.

Amyloid beta 1-42 inhibits entorhinal cortex activity in the beta-gamma range: role of GSK-3.

Oscillatory activity in the entorhinal cortex has been associated with several cognitive functions. Accordingly, Alzheimer Disease-associated cognitive decline has been related to amyloid beta-induced disturbances in several of these oscillatory patterns. We have previously shown that acute application of amyloid beta inhibits the generation of slow frequency oscillations (7-20 Hz). In contrast, alterations in faster oscillations recorded in Alzheimer Disease-transgenic mice that over-express amyloid beta have been controversial. Since transgenic mice may produce complex responses due to compensatory mechanisms, we tested the effect of acute application of amyloid beta on fast oscillations (beta-gamma bursts) generated by entorhinal cortex slices in vitro in a Mg2+ -ree solution. We also explored the participation of the enzyme glycogen synthase kinase 3 (GSK-3) in this effect. Our results show that bath application of a clinically relevant concentration of amyloid beta (10 nM) activates GSK-3 and reduces the power of beta-gamma bursts in the entorhinal cortex. The reduction of beta-gamma bursts by amyloid beta is blocked by inhibiting GSK-3 either with lithium or with SB 216763. Our results suggest that amyloid beta-induced inhibition of entorhinal cortex beta-gamma activity involves GSK-3 activation, which may provide a molecular mechanism for amyloid beta-induced neural network disruption and support the use of GSK-3 inhibitors to treat Alzheimer Disease.

Encoding electric signals by Gymnotus omarorum: heuristic modeling of tuberous electroreceptor organs.

The role of different substructures of electroreceptor organs in signal encoding was explored using a heuristic computational model. This model consists of four modules representing the pre-receptor structures, the transducer cells, the synapses and the afferent fiber, respectively. Simulations reproduced previously obtained experimental data. We showed that different electroreceptor types described in the literature can be qualitative modeled with the same set of equations by changing only two parameters, one affecting the filtering properties of the pre-receptor, and the other affecting the transducer module. We studied the responses of different electroreceptor types to natural stimuli using simulations derived from an experimentally-obtained database in which the fish were exposed to resistive or capacitive objects. Our results indicate that phase and frequency spectra are differentially encoded by different subpopulations of tuberous electroreceptors. A different type of receptor responses to the same input is a necessary condition for encoding a multidimensional space of stimuli as in the waveform of the EOD. Our simulation analysis suggested that the electroreceptive mosaic may perform a waveform analysis of electrosensory signals. As in color vision or tactile texture perception, a secondary attribute, "electric color" may be encoded as a parallel activity of various electroreceptor types. This article is part of a Special Issue entitled Neural Coding.

Differential roles of NMDA Receptor Subtypes NR2A and NR2B in dendritic branch development and requirement of RasGRF1.

N-methyl-D-aspartate receptors (NMDARs) are known to regulate axonal refinement and dendritic branching. However, because NMDARs are abundantly present as tri-heteromers (e.g., NR1/NR2A/NR2B) during development, the precise role of the individual subunits NR2A and NR2B in these processes has not been elucidated. Ventral spinal cord neurons (VSCNs) provide a unique opportunity to address this problem, because the expression of both NR2A and NR2B (but not NR1) is downregulated in culture. Exogenous NR2A or NR2B were introduced into these naturally NR2-null neurons at 4 DIV, and electrophysiological recordings at 11 DIV confirmed that synaptic NR1NR2A receptors and NR1NR2B receptors were formed, respectively. Analysis of the dendritic architecture showed that introduction of NR2B, but not NR2A, dramatically increased the number of secondary and tertiary dendritic branches of VSCNs. Whole cell patch-clamp recordings further indicated that the newly formed branches in NR2B-expressing neurons were able to establish functional synapses because the frequency of miniature AMPA-receptor synaptic currents was increased. Using previously described mutants, we also found that disruption of the interaction between NR2B and RasGRF1 dramatically impaired dendritic branch formation in VSCNs. The differential role of the NR2A and NR2B subunits and the requirement for RasGRF1 in regulating branch formation was corroborated in hippocampal cultures. We conclude that the association between NR1NR2B-receptors and RasGRF1 is needed for dendritic branch formation in VSCNs and hippocampal neurons in vitro. The dominated NR2A expression and the limited interactions of this subunit with the signaling protein RasGRF1 may contribute to the restricted dendritic arbor development in the adult CNS.

Wnt-5a/JNK signaling promotes the clustering of PSD-95 in hippocampal neurons.

During the formation of synapses, specific regions of pre- and postsynaptic cells associate to form a single functional transmission unit. In this process, synaptogenic factors are necessary to modulate pre- and postsynaptic differentiation. In mammals, different Wnt ligands operate through canonical and non-canonical Wnt pathways, and their precise functions to coordinate synapse structure and function in the mature central nervous system are still largely unknown. Here, we studied the effect of different Wnt ligands on postsynaptic organization. We found that Wnt-5a induces short term changes in the clustering of PSD-95, without affecting its total levels. Wnt-5a promotes the recruitment of PSD-95 from a diffuse dendritic cytoplasmic pool to form new PSD-95 clusters in dendritic spines. Moreover, Wnt-5a acting as a non-canonical ligand regulates PSD-95 distribution through a JNK-dependent signaling pathway, as demonstrated by using the TAT-TI-JIP peptide in mature hippocampal neurons. Finally, using adult rat hippocampal slices, we found that Wnt-5a modulates glutamatergic synaptic transmission through a postsynaptic mechanism. Our studies indicate that the Wnt-5a/JNK pathway modulates the postsynaptic region of mammalian synapse directing the clustering and distribution of the physiologically relevant scaffold protein, PSD-95.

Inhibitory contribution to suprathreshold corticostriatal responses: an experimental and modeling study.

Neostriatal neurons may undergo events of spontaneous synchronization as those observed in recurrent networks of excitatory neurons, even when cortical afferents are transected. It is necessary to explain these events because the neostriatum is a recurrent network of inhibitory neurons. Synchronization of neuronal activity may be caused by plateau-like depolarizations. Plateau-like orthodromic depolarizations that resemble up-states in medium spiny neostriatal neurons (MSNs) may be induced by a single corticostriatal suprathreshold stimulus. Slow synaptic depolarizations may last hundreds of milliseconds, decay slower than the monosynaptic glutamatergic synaptic potentials that induce them, and sustain repetitive firing. Because inhibitory inputs impinging onto MSNs have a reversal potential above the resting membrane potential but below the threshold for firing, they conform a type of "shunting inhibition". This work asks if shunting GABAergic inputs onto MSNs arrive asynchronously enough as to help in sustaining the plateau-like corticostriatal response after a single cortical stimulus. This may help to begin explaining autonomous processing in the striatal micro-circuitry in the presence of a tonic excitatory drive and independently of spatio-temporally organized inputs. It is shown here that besides synaptic currents from AMPA/KA- and NMDA-receptors, as well as L-type intrinsic Ca(2+)- currents, inhibitory synapses help in maintaining the slow depolarization, although they accomplish the role of depressing firing at the beginning of the response. We then used a NEURON model of spiny cells to show that inhibitory synapses arriving asynchronously on the dendrites can help to simulate a plateau potential similar to that observed experimentally.