Modeling the spatiotemporal intracellular calcium dynamics in nerve cell with strong memory effects

Calcium signaling in nerve cells is a crucial activity for the human brain to execute a diversity of its functions. An alteration in the signaling process leads to cell death. To date, several attempts registered to study the calcium distribution in nerve cells like neurons, astrocytes, etc. in the form of the integer-order model. In this paper, a fractional-order mathematical model to study the spatiotemporal profile of calcium in nerve cells is assembled and analyzed. The proposed model is solved by the finite element method for space derivative and finite difference method for time derivative. The classical case of the calcium dynamics model is recovered by setting the fractional parameter and that validates the model for classical sense. The numerical computations have systematically presented the impact of a fractional parameter on nerve cells. It is observed that calbindin-D28k provides a significant effect on the spatiotemporal variation of calcium profile due to the amalgamation of the memory of nerve cells. The presence of excess amounts of calbindin-D28k controls the intracellular calcium level and prevents the nerve cell from toxicity.

Postnatal Cytoarchitecture and Neurochemical Hippocampal Dysfunction in Down Syndrome

Although the prenatal hippocampus displays deficits in cellular proliferation/migration and volume, which are later associated with memory deficits, little is known about the effects of trisomy 21 on postnatal hippocampal cellular development in Down syndrome (DS). We examined postnatal hippocampal neuronal profiles from autopsies of DS and neurotypical (NTD) neonates born at 38-weeks’-gestation up to children 3 years of age using antibodies against non-phosphorylated (SMI-32) and phosphorylated (SMI-34) neurofilament, calbindin D-28k (Calb), calretinin (Calr), parvalbumin (Parv), doublecortin (DCX) and Ki-67, as well as amyloid precursor protein (APP), amyloid beta (Aβ) and phosphorylated tau (p-tau). Although the distribution of SMI-32-immunoreactive (-ir) hippocampal neurons was similar at all ages in both groups, pyramidal cell apical and basal dendrites were intensely stained in NTD cases. A greater reduction in the number of DCX-ir cells was observed in the hippocampal granule cell layer in DS. Although the distribution of Calb-ir neurons was similar between the youngest and oldest NTD and DS cases, Parv-ir was not detected. Conversely, Calr-ir cells and fibers were observed at all ages in DS, while NTD cases displayed mainly Calr-ir fibers. Hippocampal APP/Aβ-ir diffuse-like plaques were seen in DS and NTD. By contrast, no Aβ1–42 or p-tau profiles were observed. These findings suggest that deficits in hippocampal neurogenesis and pyramidal cell maturation and increased Calr immunoreactivity during early postnatal life contribute to cognitive impairment in DS.

Application of the Mirror Technique for Three-Dimensional Electron Microscopy of Neurochemically Identified GABA-ergic Dendrites

In the nervous system synaptic input arrives chiefly on dendrites and their type and distribution have been assumed pivotal in signal integration. We have developed an immunohistochemistry (IH)-correlated electron microscopy (EM) method – the “mirror” technique – by which synaptic input to entire dendrites of neurochemically identified interneurons (INs) can be mapped due preserving high-fidelity tissue ultrastructure. Hence, this approach allows quantitative assessment of morphometric parameters of synaptic inputs along the whole length of dendrites originating from the parent soma. The method exploits the fact that adjoining sections have truncated or cut cell bodies which appear on the common surfaces in a mirror fashion. In one of the sections the histochemical marker of the GABAergic subtype, calbindin was revealed in cell bodies whereas in the other section the remaining part of the very same cell bodies were subjected to serial section EM to trace and reconstruct the synaptology of entire dendrites. Here, we provide exemplary data on the synaptic coverage of two dendrites belonging to the same calbindin-D28K immunopositive IN and determine the spatial distribution of asymmetric and symmetric synapses, surface area and volume of the presynaptic boutons, morphometric parameters of synaptic vesicles, and area extent of the active zones.

Cerebellar Calcium-Binding Protein and Neurotrophin Receptor Defects in Down Syndrome and Alzheimer's Disease

Cerebellar hypoplasia is a major characteristic of the Down syndrome (DS) brain. However, the consequences of trisomy upon cerebellar Purkinje cells (PC) and interneurons in DS are unclear. The present study performed a quantitative and qualitative analysis of cerebellar neurons immunostained with antibodies against calbindin D-28k (Calb), parvalbumin (Parv), and calretinin (Calr), phosphorylated and non-phosphorylated intermediate neurofilaments (SMI-34 and SMI-32), and high (TrkA) and low (p75NTR) affinity nerve growth factor (NGF) receptors as well as tau and amyloid in DS (n = 12), Alzheimer's disease (AD) (n = 10), and healthy non-dementia control (HC) (n = 8) cases. Our findings revealed higher Aβ42 plaque load in DS compared to AD and HC but no differences in APP/Aβ plaque load between HC, AD, and DS. The cerebellar cortex neither displayed Aβ40 containing plaques nor pathologic phosphorylated tau in any of the cases examined. The number and optical density (OD) measurements of Calb immunoreactive (-ir) PC soma and dendrites were similar between groups, while the number of PCs positive for Parv and SMI-32 were significantly reduced in AD and DS compared to HC. By contrast, the number of SMI-34-ir PC dystrophic axonal swellings, termed torpedoes, was significantly greater in AD compared to DS. No differences in SMI-32- and Parv-ir PC OD measurements were observed between groups. Conversely, total number of Parv- (stellate/basket) and Calr (Lugaro, brush, and Golgi)-positive interneurons were significantly reduced in DS compared to AD and HC. A strong negative correlation was found between counts for Parv-ir interneurons, Calr-ir Golgi and brush cells, and Aβ42 plaque load. Number of TrkA and p75NTR positive PCs were reduced in AD compared to HC. These findings suggest that disturbances in calcium binding proteins play a critical role in cerebellar neuronal dysfunction in adults with DS.

Changes in the Population Size of Calbindin D-28k-Immunoreactive Enteric Neurons in the Porcine Caecum under the Influence of Bisphenol A: A Preliminary Study

Calbindin D-28k (CB) is a calcium-binding protein widely distributed in living organisms that may act as a calcium buffer and sensory protein. CB is present in the enteric nervous system (ENS) situated in the gastrointestinal tract, which controls the majority of activities of the stomach and intestine. The influence of various doses of bisphenol A (BPA)—a chemical compound widely used in plastics production—on the number and distribution of CB-positive enteric neuronal cells in the porcine caecum was investigated with an immunofluorescence technique. The obtained results showed that low dosages of BPA resulted in an increase in the number of CB-positive neuronal cells in the myenteric (MP) and inner submucous (ISP) plexuses, whereas it did not alter the number of such neuronal cells in the outer submucous plexus (OSP). High dosages of BPA caused the increase in the amount of CB-positive perikarya in all the above-mentioned kinds of the caecal neuronal plexuses. These observations strongly suggest that CB in the ENS participates in the processes connected with the toxic activity of BPA. Most likely, the changes noted in this experiment result from the adaptive and protective properties of CB.

An updated investigation on the dromedary camel cerebellum (Camelus dromedarius) with special insight into the distribution of calcium-binding proteins

Studying the cerebella of different animals is important to expand the knowledge about the cerebellum. Studying the camel cerebellum was neglected even though the recent research in the middle east and Asia. Therefore, the present study was designed to achieve a detailed description of the morphology and the cellular organization of the camel cerebellum. Because of the high importance of the calcium ions as a necessary moderator the current work also aimed to investigate the distribution of calcium binding proteins (CaBP) such as calbindin D-28K (CB), parvalbumin (PV) and calretinin (CR) in different cerebellar cells including the non-traditional neurons. The architecture of camel cerebellum, as different mammals, consists of the medulla and three layered-cortex. According to our observation the cells in the granular layer were not crowded and many spaces were observed. CB expression was the highest by Purkinje cells including their dendritic arborization. In addition to its expression by the inhibitory interneurons (basket, stellate and Golgi neurons), it is also expressed by the excitatory granule cells. PV was expressed by Purkinje cells, including their primary arborization, and by the molecular layer cells. CR immunoreactivity (-ir) was obvious in almost all cell layers with varying degrees, however a weak or any expression by the Purkinje cells. The molecular layer cells and the Golgi and the non traditional large neurons of the granular layer showed the strongest CR-ir. Granule neurons showed moderate immunoreactivity for CB and CR. In conclusion, the results of the current study achieved a complete map for the neurochemical organization of CaBP expression and distribution by different cells in the camel cerebellum.

Benefits and constrains of covalency: the role of loop length in protein stability and ligand binding

Protein folding is governed by non-covalent interactions under the benefits and constraints of the covalent linkage of the backbone chain. In the current work we investigate the influence of loop length variation on the free energies of folding and ligand binding in a small globular single-domain protein containing two EF-hand subdomains—calbindin D9k. We introduce a linker extension between the subdomains and vary its length between 1 to 16 glycine residues. We find a close to linear relationship between the linker length and the free energy of folding of the Ca2+-free protein. In contrast, the linker length has only a marginal effect on the Ca2+ affinity and cooperativity. The variant with a single-glycine extension displays slightly increased Ca2+ affinity, suggesting that the slightly extended linker allows optimized packing of the Ca2+-bound state. For the extreme case of disconnected subdomains, Ca2+ binding becomes coupled to folding and assembly. Still, a high affinity between the EF-hands causes the non-covalent pair to retain a relatively high apparent Ca2+ affinity. Our results imply that loop length variation could be an evolutionary option for modulating properties such as protein stability and turnover without compromising the energetics of the specific function of the protein.