Synapse formation: let's stick together

Synapse formation requires the precise alignment and attachment of presynaptic and postsynaptic cells. Homophilic cell adhesion molecules have now been found to have a role in these processes on both sides of the synaptic cleft.     

Molecular and cellular mechanisms of human cortical connectivity

Comparative studies of the cerebral cortex have identified various human and primate-specific changes in both local and long-range connectivity, which are thought to underlie our advanced cognitive capabilities. These changes are likely mediated by the divergence of spatiotemporal regulation of gene expression, which is particularly prominent in the prenatal and early postnatal human and non-human primate cerebral cortex. In this review, we describe recent advances in characterizing human and primate genetic and cellular innovations including identification of novel species-specific, especially human-specific, genes, gene expression patterns, and cell types. Finally, we highlight three recent studies linking these molecular changes to reorganization of cortical connectivity.     

Combinatorial microRNAs: Working together to make a difference

MicroRNAs regulate gene networks and therefore are inherently complex. MicroRNAs themselves function in networks of other microRNAs, some of which are co-expressed from the same locus. To better understand the interplay among microRNAs that underlies their functions, we examined the potential of combinatorial effects of endogenously and exogenously co-expressed microRNAs. In this review, we first distill the similarities and differences between three microRNA families that function in cell division, miR-16, miR-34a and miR-106b, with emphasis on their exquisite phenotypic diversity. Given that the microRNAs affect cell cycle progression via distinct targets, we tested for phenotypic synergism among them. Furthermore, we investigate target regulation by individual and pooled microRNAs to gain insight into interactions among microRNAs co-expressed from the same chromosomal locus. The ability of microRNAs to modulate multiple genes within a molecular pathway engenders a novel way of thinking about targeting pathways: instead of a one-inhibitor-one-target model, multiple components in a pathway can be modulated by a microRNA resulting in a potent yet reversible inhibition of the pathway. To fully realize this potential, we need to understand how microRNAs function singly and in concert with each other.     

Role of cholinergic mechanisms in the genesis of some cortical responses

The dynamics of evoked potentials during blocking of cholinergic cortical structures was investigated in unanesthetized cats. Application of the anticholinergic drug benactyzine inhibits the negative phases of cortical responses to stimulation of the reticular formation and non-specific thalamic nuclei and also of responses to direct cortical stimulation. Direct cortical responses (DCRs), inverted by -aminobutyric acid, are also depressed, indicating the role of cholinergic mechanisms in the genesis of these responses. During blocking of cholinergic synapses, negative phases of the primary response (PR) and response to stimulation of the specific thalamic nucleus are facilitated. A tendency is then observed toward grouping of spontaneous unit discharges and abolition of inhibition of cortical neurons produced by high-frequency stimulation of the reticular formation. One cause of the increase in amplitude of the primary response (PR) to the action of anticholinergic drugs may be widening of the zone of cortical neurons involved in the response because of abolition of the localizing effect of inhibitory neurons.Institute of Physiology, Siberian Division, Academy of Sciences of the USSR, Novosibirsk. Translated from Neirofiziologiya, Vol. 2, No. 4, pp. 406–411, July–August, 1970.     

Dynamics of functional connectivity in visual cortical networks: An overview

The aim of the Royaumont Symposium was to review various dynamic aspects of adaptive changes in functional connectivity, expressed in cortical networks during development, learning, and possibly during recognition and cognitive processing. The link between the various experimental and theoretical models was the comparison of cellular and molecular mechanisms that could be involved in the up- and down-regulation of functional connectivity, over different time scales. These processes have been investigated using several approaches in parallel: 1) at the molecular/subcellular level, to identify postsynaptic receptors (NMDA, mGluR) and second messengers (calcium, protein kinases and phosphatases) involved in the induction of synaptic potentiation and depression, and to characterize diffusible factors (NO), released pre- or postsynaptically, involved in the spatial generalization of local changes to neighboring synapses; 2) at the level of integrating networks, to develop electrophysiological (single and multiple recording), pharmacological and optical imaging techniques in order to compare the dynamics of adaptive processes put into play during the natural development of cortical specificity and connectivity, versus those triggered during forced regimes of temporal correlations between pre- and post synaptic activities. Both in vitro and in vivo approaches have been combined in the primary visual cortex of the developing and adult vertebrate (rat, guinea-pig, ferret, cat and monkey). The various forms of ‘slow’ synaptic plasticity, demonstrated during epigenesis and selective phases of learning in the adult, can be compared with ‘fast’ forms of functional coupling (or synchronous firing) shown to develop during the time span required for perception and cognitive processing. Phenomenology of the dynamics in functional connectivity and their relative dependence on temporal correlation in neuronal activity have been analyzed in each of these situations. Experimental results have been compared at different levels of neuronal integration (synapse, column, map and cell assembly) in order to gain a better understanding of functional grouping within cortical networks.     

Quantitative measures of cortical functional connectivity: A state-of-the-art brief survey

The modern concepts of quantitative measurement of the strength of functional and effective cortical connectivity in neurocognitive networks (large-scale distributed brain systems of interacting neuronal populations that are believed to underlie cognitive processing) are reviewed. The two main classes of the methods of connectivity assessment (linear and nonlinear) are discussed. In the class of linear methods, in addition to coherence routinely used to measure the strength of functional links, the vector autoregressive modeling of multichannel EEG is discussed in detail. The latter technique allows the estimation of both functional and effective connectivity, i.e., the measures such as directed transfer function (DTF) and direct partial coherence (PDC) extensively used in cognitive neuroscience. The impact of volume conduction on different estimates of connectivity is considered and the imaginary part of complex-valued coherence as a way to reduce the artificial influence of volume conduction is discussed. Independent component analysis (ICA) and transfer entropy as a method of estimating direct influence are reviewed in the class of nonlinear methods.     

Visuomotor transformations: early cortical mechanisms of reaching

Recent studies of visually guided reaching in monkeys support the hypothesis that the visuomotor transformations underlying arm movements to spatial targets involve a parallel mechanism that simultaneously engages functionally related frontal and parietal areas linked by reciprocal cortico-cortical connections. The neurons in these areas possess similar combinations of response properties. The multimodal combinatorial properties of these neurons and the gradient architecture of the parieto-frontal network emerge as a potential substrate to link the different sensory and motor signals that arise during reaching behavior into common hybrid reference frames. This convergent combinatorial process is evident at early stages of visual information processing in the occipito-parietal cortex, suggesting the existence of re-entrant motor influences on cortical areas once believed to have only visual functions.     

Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

Background

The 26S proteasome is at the heart of the ubiquitin-proteasome system, which is the key cellular pathway for the regulated degradation of proteins and enforcement of protein quality control. The 26S proteasome is an unusually large and complicated protease comprising a 28-subunit core particle (CP) capped by one or two 19-subunit regulatory particles (RP). Multiple activities within the RP process incoming ubiquitinated substrates for eventual degradation by the barrel-shaped CP. The large size and elaborate architecture of the proteasome have made it an exceptional model for understanding mechanistic themes in macromolecular assembly.

Objective

In the present work, we highlight the most recent mechanistic insights into proteasome assembly, with particular emphasis on intrinsic and extrinsic factors regulating proteasome biogenesis. We also describe new and exciting questions arising about how proteasome assembly is regulated and deregulated in normal and diseased cells.

Methods

A comprehensive literature search using the PubMed search engine was performed, and key findings yielding mechanistic insight into proteasome assembly were included in this review.

Results

Key recent studies have revealed that proteasome biogenesis is dependent upon intrinsic features of the subunits themselves as well as extrinsic factors, many of which function as dedicated chaperones.

Conclusion

Cells rely on a diverse set of mechanistic strategies to ensure the rapid, efficient, and faithful assembly of proteasomes from their cognate subunits. Importantly, physiological as well as pathological changes to proteasome assembly are emerging as exciting paradigms to alter protein degradation in vivo.

     

Cardiac channelopathies: Genetic and molecular mechanisms

Channelopathies are diseases caused by dysfunctional ion channels, due to either genetic or acquired pathological factors. Inherited cardiac arrhythmic syndromes are among the most studied human disorders involving ion channels. Since seminal observations made in 1995, thousands of mutations have been found in many of the different genes that code for cardiac ion channel subunits and proteins that regulate the cardiac ion channels. The main phenotypes observed in patients carrying these mutations are congenital long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS) and variable types of conduction defects (CD). The goal of this review is to present an update of the main genetic and molecular mechanisms, as well as the associated phenotypes of cardiac channelopathies as of 2012.     

Specificity of cortical synaptic connectivity: Emphasis on perspectives gained from quantitative electron microscopy

This report traces the historical development of concepts regarding the specificity of synaptic connectivity in the cerebral cortex as viewed primarily from the perspective of electron microscopy. The occurrence of stereotypical patterns of connection (e.g., contrasting synaptic patterns on the surfaces of spiny vs. non-spiny neurons, the general consistency with which axonal pathways impinge on and originate within specific cortical areas and layers, triadic synaptic relationships) implies that cortical connectivity is highly structured. The high degree of order characterizing many aspects of cortical organization is mirrored by an equally ordered arrangement of synaptic connections between specific types of neurons. This observation is based on quantitative electron microscopic studies of synapses between identified neurons and from the results of correlative anatomical/electrophysiological investigations. The recognition of recurring synaptic patterns and responses between specific neurons has generated increased support for the notion of specificity of synaptic connections at the expense of randomness, but the role of specificity in cortical function is an unresolved question. At the core of cortical processing lie myriad possibilities for computation provided by the wealth of synaptic connections involving each cortical neuron. Specificity, by limiting possibilities for connection, can impose an order on synaptic interactions even as processes of dynamic selection or synaptic remodeling ensure the constant formation and dissolution of cortical circuits. These operations make maximal use of the richness of cortical synaptic connections to produce a highly flexible system, irrespective of the degree of randomness or specificity that obtains for cortical wiring at any particular time.     

Birds of a feather winter together: migratory connectivity in the Reed Warbler Acrocephalus scirpaceus

To investigate migratory connectivity in the Reed Warbler Acrocephalus scirpaceus, we analysed (1) all available sub-Saharan ringing recoveries and (2) stable isotopes in feathers grown in Africa sampled at 17 European breeding sites across a migratory divide. A cluster analysis of ringing recoveries showed remarkable connectivity between breeding and non-breeding grounds. Two main clusters represented populations taking the two main migratory routes [southwesterly (SW) and southeasterly (SE)]. Stable isotope analysis confirmed the separation of wintering areas of SW- and SE-migrating populations. Higher δ¹⁵N values in feathers of SE-migrating birds indicated that they occupied more xeric biome types. Values of δ¹³C that did not differ significantly among populations were higher than those from feathers of known European origin and indicated a C4 biome. Three populations with an unknown migratory direction were assigned to the SE-migrating populations on the basis of δ¹⁵N values.     

Sperm transfer mechanisms: some correlates and consequences

Abstract

The methods by which the Metazoa bring their gametes into juxtaposition as a preliminary to fertilisation are reviewed. The method of sperm transfer employed by a particular organism or group of organisms is commonly more directly related to habitat than to phylogeny. This appears in part to be a consequence of certain methods of sperm transfer facilitating the exploitation of particular habitats. Non-exposure of sperm to hostile influences such as fresh water, digestive enzymes, antibodies, or the desiccating effects of air may have been important in the colonisation of fresh waters by animals with body fluids of high osmolarity, in the establishment of the endoparasitic habit, and in the colonisation of dry land. Mutual exchange of sperm with equal sharing of the reproductive burden by means of hermaphroditism, coupled with internal fertilisation, is seen as an important adaptation to very small body size, especially as associated with life in interstitial habitats. Efficient transfer of sperm, usually in conjunction with internal fertilisation, is seen as a prerequisite for the development of yolky eggs with fairly direct development of the young. It is also a prerequisite for establishing maternal nourishment of the young in viviparity and a consequent reduction or suppression of free larval stages. Yolky eggs confer freedom from the vicissitudes of fluctuation in larval food supplies, and eggs which contain all or most of the mineral salts required for development seem necessary for colonisation of fresh waters. Amongst freshwater fishes and anurans, close pairing of male and female minimises the effects of rapid destruction of sperm in species which do not copulate or use spermatophores.     

Genetic connectivity across marginal habitats: the elephants of the Namib Desert

Locally isolated populations in marginal habitats may be genetically distinctive and of heightened conservation concern. Elephants inhabiting the Namib Desert have been reported to show distinctive behavioral and phenotypic adaptations in that severely arid environment. The genetic distinctiveness of Namibian desert elephants relative to other African savanna elephant (Loxodonta africana) populations has not been established. To investigate the genetic structure of elephants in Namibia, we determined the mitochondrial (mt) DNA control region sequences and genotyped 17 microsatellite loci in desert elephants (n = 8) from the Hoanib River catchment and the Hoarusib River catchment. We compared these to the genotypes of elephants (n = 77) from other localities in Namibia. The mtDNA haplotype sequences and frequencies among desert elephants were similar to those of elephants in Etosha National Park, the Huab River catchment, the Ugab River catchment, and central Kunene, although the geographically distant Caprivi Strip had different mtDNA haplotypes. Likewise, analysis of the microsatellite genotypes of desert‐dwelling elephants revealed that they were not genetically distinctive from Etosha elephants, and there was no evidence for isolation by distance across the Etosha region. These results, and a review of the historical record, suggest that a high learning capacity and long‐distance migrations allowed Namibian elephants to regularly shift their ranges to survive in the face of high variability in climate and in hunting pressure.