Polysialic acids: potential in improving the stability and pharmacokinetics of proteins and other therapeutics

Naturally occurring polymers of N-acetylneuraminic acid (polysialic acids) are biodegradable, highly hydrophilic and have no known receptors in the body. Following intravenous injection, polysialic acids exhibit long half-lives in the blood circulation and have therefore been proposed as carriers of short-lived drugs and small peptides. In addition, shorter-chain polysialic acids can be used as a means to increase the circulatory half-life of proteins and thus serve as an alternative to the nonbiodegradable monomethoxypoly(ethylene glycol). Recent work has shown that covalent coupling of a low molecular weight polysialic acid (colominic acid) to catalase and asparaginase leads to a considerable increase of enzyme stability in the presence of proteolytic enzymes or blood plasma. Comparative studies in vivo with polysialylated and intact asparaginase revealed that polysialylation significantly increases the half-life of the enzyme. The highly hydrophilic and innocuous nature of polysialic acids renders them suitable as a means to prolong the circulation of peptides and proteins.     

Synaptic integration by different dendritic compartments of hippocampal CA1 and CA2 pyramidal neurons

Pyramidal neurons have a complex dendritic arbor containing tens of thousands of synapses. In order for the somatic/axonal membrane potential to reach action potential threshold, concurrent activation of multiple excitatory synapses is required. Frequently, instead of a simple algebraic summation of synaptic potentials in the soma, different dendritic compartments contribute to the integration of multiple inputs, thus endowing the neuron with a powerful computational ability. Most pyramidal neurons share common functional properties. However, different and sometimes contrasting dendritic integration rules are also observed. In this review, we focus on the dendritic integration of two neighboring pyramidal neurons in the hippocampus: the well-characterized CA1 and the much less understood CA2. The available data reveal that the dendritic integration of these neurons is markedly different even though they are targeted by common inputs at similar locations along their dendrites. This contrasting dendritic integration results in different routing of information flow and generates different corticohippocampal loops.     

Soluble polysialylated NCAM: a novel player of the innate immune system in the lung

Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing “neutrophil extracellular traps”, which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes.     

Determination of the connectivity of newborn neurons in mammalian olfactory circuits

The mammalian olfactory bulb is a forebrain structure just one synapse downstream from the olfactory sensory neurons and performs the complex computations of sensory inputs. The formation of this sensory circuit is shaped through activity-dependent and cell-intrinsic mechanisms. Recent studies have revealed that cell-type specific connectivity and the organization of synapses in dendritic compartments are determined through cell-intrinsic programs already preset in progenitor cells. These progenitor programs give rise to subpopulations within a neuron type that have distinct synaptic organizations. The intrinsically determined formation of distinct synaptic organizations requires factors from contacting cells that match the cell-intrinsic programs. While certain genes control wiring within the newly generated neurons, other regulatory genes provide intercellular signals and are only expressed in neurons that will form contacts with the newly generated cells. Here, the olfactory system has provided a useful model circuit to reveal the factors regulating assembly of the highly structured connectivity in mammals.     

Coexistence of peptides with classical neurotransmitters

Summary In the present article the fact is emphasized that neuropeptides often are located in the same neurons as classical transmitters such as acetylcholine, 5-hydroxy-tryptamine, catecholamines, -aminobutyric acid (GABA) etc. This raises the possibility that neurons produce, store and release more than the one messenger molecule. The exact functional role of such coesisting peptides is often difficult to evaluate, especially in the central nervous system. In the periphery some studies indicate apparently meaningful interactions of different types with the classical transmitter, but other types of actions including trophic effects have been observed. More recently it has been shown that some neurons contain more than one classical transmitter, e.g. 5-HT plus GABA, further underlining the view that transfer of information across synapses may be more compex than perhaps hitherto assumed.     

Neurotrophins and neuronal differentiation in the central nervous system

The central nervous system requires the proper formation of exquisitely precise circuits to function properly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. For these circuits to form correctly, neurons must elaborate precisely patterned axonal and dendritic arbors. Although the cellular and molecular mechanisms that guide neuronal differentiation and formation of connections remain mostly unknown, the neurotrophins have emerged recently as attractive candidates for regulating neuronal differentiation in the developing brain. The experiments reviewed here provide strong support for a bifunctional role for the neurotrophins in axonal and dendritic growth and are consistent with the exciting possibility that the neurotrophins might mediate activity-dependent synaptic plasticity.     

Metallothionein promotes regenerative axonal sprouting of dorsal root ganglion neurons after physical axotomy

Prior studies have reported that metallothionein I/II (MT) promote regenerative axonal sprouting and neurite elongation of a variety of central nervous system neurons after injury. In this study, we evaluated whether MT is capable of modulating regenerative axon outgrowth of neurons from the peripheral nervous system. The effect of MT was firstly investigated in dorsal root ganglion (DRG) explants, where axons were scratch-injured in the presence or absence of exogenous MT. The application of MT led to a significant increase in regenerative sprouting of neurons 16 h after injury. We show that the pro-regenerative effect of MT involves an interaction with the low-density lipoprotein receptor megalin, which could be blocked using the competitive antagonist RAP. Pre-treatment with the mitogen-activated protein kinase (MAPK) inhibitor PD98059 also completely abrogated the effect of exogenous MT in promoting axonal outgrowth. Interestingly, we only observed megalin expression in neuronal soma and not axons in the DRG explants. To investigate this matter, an in vitro injury model was established using Campenot chambers, which allowed the application of MT selectively into either the axonal or cell body compartments after scratch injury was performed to axons. At 16 h after injury, regenerating axons were significantly longer only when exogenous MT was applied solely to the soma compartment, in accordance with the localized expression of megalin in neuronal cell bodies. This study provides a clear indication that MT promotes axonal regeneration of DRG neurons, via a megalin- and MAPK-dependent mechanism.     

Tachykinins and their functions in the gastrointestinal tract

In the gastrointestinal tract, tachykinins are peptide neurotransmitters in nerve circuits that regulate intestinal motility, secretion, and vascular functions. Tachykinins also contribute to transmission from spinal afferents that innervate the gastrointestinal tract and have roles in the responses of the intestine to inflammation. Tachykinins coexist with acetylcholine, the primary transmitter of excitatory neurons innervating the muscle, and act as a co-neurotransmitter of excitatory neurons. Excitatory transmission is mediated through NK1 receptors (primarily on interstitial cells of Cajal) and NK2 receptors on the muscle. Tachykinins participate in slow excitatory transmission at neuro-neuronal synapses, through NK1 and NK3 receptors, in both ascending and descending pathways affecting motility. Activation of receptors (NK1 and NK2) on the epithelium causes fluid secretion. Tachykinin receptors on immune cells are activated during inflammation of the gut. Finally, tachykinins are released from the central terminals of gastrointestinal afferent neurons in the spinal cord, particularly in nociceptive pathways. Received 24 March 2007; received after revision 30 August 2007; accepted 14 September 2007     

Localization and stabilization of ionotropic glutamate receptors at synapses

Appropriate targeting and clustering of ionotropic glutamate receptors (iGluRs) is critical for the formation and maintenance of excitatory synapses. Recent studies have demonstrated that the synaptic localization of iGluR subtypes is remarkably heterogeneous and subject to regulation over time scales ranging from minutes to months. These findings, together with the identification of key protein binding partners of iGluRs, have opened a window onto the complex cell biology of iGluR membrane trafficking. In this article, we review recent findings on the cellular and molecular mechanisms involved in localizing iGluRs at synapses and discuss their implications for synaptogenesis and synaptic plasticity.     

Altered axon terminals containing concentric lamellar bodies of cerebellar Pukinje cells in Mongolian gerbil

Altered axon terminals containing concentric lamellar bodies were observed in cerebellar and vestibular nuclei of the Mongolian gerbil. The terminals increased in number from 30 days of age onward, and reached about tenfold at 360 days. The numbers were the same in two gerbil strains with different susceptibility to spontaneous motor seizures by various stimuli, but about threefold those in Slc:Wistar rat.     

Thermoadaptive influence on reactivity pattern of vasopressinergic neurons in the guinea pig

Summary In cold-adapted guinea pigs, increased amounts of arginine-vasopressin (AVP) immunoreactive material could be visualized in neurons of the supraoptic and paraventricular nucleus, in fibers projecting to the neurohypophysis and in fiber terminals in the ventral lateral septum and in the amygdala. In warm-adapted animals the reactivity to AVP antiserum was poor in all neuronal structures examined. High AVP-immunoreactivity was accompanied by a reduced febrile response to bacterial pyrogen in cold-adapted guinea pigs.     

Thermoadaptive influence on reactivity pattern of vasopressinergic neurons in the guinea pig

In cold-adapted guinea pigs, increased amounts of arginine-vasopressin (AVP) immunoreactive material could be visualized in neurons of the supraoptic and paraventricular nucleus, in fibers projecting to the neurohypophysis and in fiber terminals in the ventral lateral septum and in the amygdala. In warm-adapted animals the reactivity to AVP antiserum was poor in all neuronal structures examined. High AVP-immunoreactivity was accompanied by a reduced febrile response to bacterial pyrogen in cold-adapted guinea pigs.     

CDK5 downregulation enhances synaptic plasticity

CDK5 is a serine/threonine kinase that is involved in the normal function of the adult brain and plays a role in neurotransmission and synaptic plasticity. However, its over-regulation has been associated with Tau hyperphosphorylation and cognitive deficits. Our previous studies have demonstrated that CDK5 targeting using shRNA-miR provides neuroprotection and prevents cognitive deficits. Dendritic spine morphogenesis and forms of long-term synaptic plasticity—such as long-term potentiation (LTP)—have been proposed as essential processes of neuroplasticity. However, whether CDK5 participates in these processes remains controversial and depends on the experimental model. Using wild-type mice that received injections of CDK5 shRNA-miR in CA1 showed an increased LTP and recovered the PPF in deficient LTP of APPswe/PS1Δ9 transgenic mice. On mature hippocampal neurons CDK5, shRNA-miR for 12 days induced increased dendritic protrusion morphogenesis, which was dependent on Rac activity. In addition, silencing of CDK5 increased BDNF expression, temporarily increased phosphorylation of CaMKII, ERK, and CREB; and facilitated calcium signaling in neurites. Together, our data suggest that CDK5 downregulation induces synaptic plasticity in mature neurons involving Ca²⁺ signaling and BDNF/CREB activation.     

Selective representation of vibrissa at the level of cerebellar Purkinje cells by way of climbing fibers in rats]

In the Rat peripheral information from snout vibrissae are transmitted to cerebellar Purkinje cells of Crus I and II by both mossy and climbing fibers. The climbing fiber pathway is organized in a very precise manner, a particular Purkinje cell being preferentially activated by a single vibrissa.     

Coexistence of peptides with classical neurotransmitters

In the present article the fact is emphasized that neuropeptides often are located in the same neurons as classical transmitters such as acetylcholine, 5-hydroxy-tryptamine, catecholamines, gamma-aminobutyric acid (GABA) etc. This raises the possibility that neurons produce, store and release more than one messenger molecule. The exact functional role of such coexisting peptides is often difficult to evaluate, especially in the central nervous system. In the periphery some studies indicate apparently meaningful interactions of different types with the classical transmitter, but other types of actions including trophic effects have been observed. More recently it has been shown that some neurons contain more than one classical transmitter, e.g. 5-HT plus GABA, further underlining the view that transfer of information across synapses may be more complex than perhaps hitherto assumed.