Simple spiking networks to investigate pathophysiological basis of abnormal cortical oscillations in Alzheimer’s disease

This research outlined here is focused on developing a better understanding of the pathophysiological causes of abnormal cortical oscillations in Alzheimer’s disease using simple spiking networks. Spiking dynamics of neurons were simulated based on Izhikevich’s model of spiking neurons. This phenomenological model exhibits spatiotemporal dynamics and collective waves of oscillations of local field potentials in the delta, alpha and beta ranges, similar to that observed from the normal brain. The simulated network consists of 1,000 neurons of different types; fully and randomly connected to each other (no synaptic plasticity is included in this study). The network is stimulated by a random thalamic current at each time step. Some factors have been varied to test certain hypotheses such as the number of excitatory neurons (NE), the number of inhibitory neurons (NI) and an input parameter in the simple neuronal model that describes the sensitivity of the recovery variable to the subthreshold fluctuations of the membrane potential, called parameter b. Variable u accounts for the activation of K+ and inactivation of Na+ ionic currents. This study suggests a number of hypotheses for the underlying causes of abnormal activity; each hypothesis was tested by varying the values of the corresponding factor, and examines the effects of variations on the oscillatory activity of the network. For each step, we have simulated a group of ten sample networks. The results were compared with a group of ten networks with normal values of all the variables (as the normal cortex); referred to as the healthy group. The Fast Fourier transform (FFT) technique has been applied on the spiking trains to analyze the neural oscillatory of the networks. Statistical tests have been used to analyze how the power spectra of each frequency band are changed by varying certain factors (P values smaller than 0.05 were considered statistically significant). When decreasing the number of excitatory neurons the alpha, beta3, gamma and full frequency bands power are significantly decreased. This finding is consistent with. Moreover, the first significant decrease started in beta3. The same behaviour appeared when decreasing parameter b for excitatory neurons. Related research demonstrated through biological experiments on cultural excitatory neurons that cortical neuronal death is mediated by the up-regulation of outward K+ current and such enhancement might specifically contribute to the pathogenesis of b-amyloid peptide (Ab)-induced neuronal death in Alzheimer’s disease. Spinal cord injury (SCI) can result in paraplegia or quadriplegia. Although no fully restorative therapies have been developed, much research is currently being conducted and various therapeutic strategies are under intense investigation. Astrocytes react in response to SCI by undergoing proliferation and migrating to the injury site, resulting in astrogliosis. The implications of these phenotypic changes are not fully understood. This study focuses on characterising astrocytic morphologies present in uninjured, contused and also contused spinal cords following treatment with Cyclosporin-A (CsA) and/or neural stem cells (NSCs). All animal experiments were conducted in accordance with local institutional and national regulations. Sprague–Dawley female rats were anaesthetised by intraperitoneal injection of ketamine and xylazine (100 and 10 mg/kg respectively) following which a laminectomy was performed at T8–T10 1,2. All animals received a 200 kilodynes moderate contusion injury at T9 using an Infinite Horizon Impactor Device. Animals were treated with CsA and/or NSCs 1 week post injury. Spinal cords were harvested 2 and 6 weeks post treatment, cryosectioned and immunohistochemically stained for astrocytic markers. Astrocytes possessing either a quiescent or reactive status are the most abundant cell type present, both 2 and 6 weeks post-injury. The astrocyte marker glial fibrillary acidic protein (GFAP) is upregulated in response to injury. CsA and NSC treatment both lead to increased GFAP expression, contributing to an elevated number of astrocytes around the lesion site. A trend toward augmented Brain lipid binding protein (BLBP) levels were observed in response to NSC treatment. Vimentin also displayed increased expression in response to treatment with NSCs. Treatment with CsA and/or NSCs offers many prospective beneficial effects. Astrocytes have shown to be heterogeneously responsive to SCI and with their reaction to CsA and NSCs, offer a potential therapeutic target by means of individual or combination therapy. The authors acknowledge grant support from the Science Foundation Ireland.

References
1. McMahon SS, Albermann S., Rooney GE, Shaw G, Garcia Y, Sweeney E, Hynes J, Dockery P, O’Brien T, Windebank AJ, Allsopp TE (2010) Barry FP Engraftment, migration and differentiation of neural stem cells in the rat spinal cord following contusion injury. Cytotherapy 12:313–325
2. McMahon SS, Albermann S, Rooney GE, Moran C, Hynes J, Garcia Y, Dockery P, O’Brien T, Windebank AJ, Barry FP (2009) Effect of cyclosporin A on functional recovery in the spinal cord following contusion injury. J Anat 215:267–279