Human cerebrospinal fluid monoclonal LGI1 autoantibodies increase neuronal excitability

OBJECTIVE: Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediatedencephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype dis-tribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. METHODS: We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from thecerebrospinalfluid (CSF) of several patients with LGI1 encephalitis. RESULTS: Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereasreactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had under-gone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with itsreceptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining,non–ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excit-ability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Interpretation: Our data show that the patients’intrathecal B-cell autoimmune response is dominated by LGI1 anti-bodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation.Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody reper-toire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides arevery distinct entities

Spermidine protects from age-related synaptic alterations at hippocampal mossy fiber-CA3 synapses

Aging is associated with functional alterations of synapses thought to contribute to age-dependent memory impairment (AMI). While therapeutic avenues to protect from AMI are largely elusive, supplementation of spermidine, a polyamine normally declining with age, has been shown to restore defective proteostasis and to protect from AMI in Drosophila. Here we demonstrate that dietary spermidine protects from age-related synaptic alterations at hippocampal mossy fiber (MF)-CA3 synapses and prevents the aging-induced loss of neuronal mitochondria. Dietary spermidine rescued age-dependent decreases in synaptic vesicle density and largely restored defective presynaptic MF-CA3 long-term potentiation (LTP) at MF-CA3 synapses (MF-CA3) in aged animals. In contrast, spermidine failed to protect CA3-CA1 hippocampal synapses characterized by postsynaptic LTP from age-related changes in function and morphology. Our data demonstrate that dietary spermidine attenuates age-associated deterioration of MF-CA3 synaptic transmission and plasticity. These findings provide a physiological and molecular basis for the future therapeutic usage of spermidine

25 Years of Self-organized Criticality: Concepts and Controversies

Introduced by the late Per Bak and his colleagues, self-organized criticality (SOC) has been one of the most stimulating concepts to come out of statistical mechanics and condensed matter theory in the last few decades, and has played a significant role in the development of complexity science. SOC, and more generally fractals and power laws, have attracted much comment, ranging from the very positive to the polemical. The other papers (Aschwanden et al. in Space Sci. Rev., 2014, this issue; McAteer et al. in Space Sci. Rev., 2015, this issue; Sharma et al. in Space Sci. Rev. 2015, in preparation) in this special issue showcase the considerable body of observations in solar, magnetospheric and fusion plasma inspired by the SOC idea, and expose the fertile role the new paradigm has played in approaches to modeling and understanding multiscale plasma instabilities. This very broad impact, and the necessary process of adapting a scientific hypothesis to the conditions of a given physical system, has meant that SOC as studied in these fields has sometimes differed significantly from the definition originally given by its creators. In Bak’s own field of theoretical physics there are significant observational and theoretical open questions, even 25 years on (Pruessner 2012). One aim of the present review is to address the dichotomy between the great reception SOC has received in some areas, and its shortcomings, as they became manifest in the controversies it triggered. Our article tries to clear up what we think are misunderstandings of SOC in fields more remote from its origins in statistical mechanics, condensed matter and dynamical systems by revisiting Bak, Tang and Wiesenfeld’s original papers

Electrophysiological and molecular characterization of the parasubiculum

The parahippocampal region is thought to be critical for memory and spatial navigation. Within this region lies the parasubiculum, a small structure that exhibits strong theta modulation, contains functionally specialised cells and projects to layer II of the medial entorhinal cortex (MEC). Thus, it is uniquely positioned to influence firing of spatially modulated cells in the MEC and play a key role in the internal representation of the external environment. However, the basic neuronal composition of the parasubiculum remains largely unknown, and its border with the MEC is often ambiguous. We combine electrophysiology and immunohistochemistry in adult mice (both sexes) to define first, the boundaries of the parasubiculum, and second, the major cell types found in this region. We find distinct differences in the colabelling of molecular markers between the parasubiculum and the MEC, allowing us to clearly separate the two structures. Moreover, we find distinct distribution patterns of different molecular markers within the PaS, across both superficial-deep and dorsal-ventral axes. Using unsupervised cluster analysis, we find that neurons in the parasubiculum can be broadly separated into three clusters based on their electrophysiological properties, and that each cluster corresponds to a different molecular marker. We demonstrate that while the PaS aligns structurally to some to general cortical principals, it also shows divergent features in particular in contrast to the MEC. This work will form an important basis for future studies working to disentangle the circuitry underlying memory and spatial navigation functions of the parasubiculum.We identify the major neuron types in the parasubiculum using immunohistochemistry and electrophysiology, and determine their distribution throughout the PaS. We find that the neuronal composition of the parasubiculum differs considerably in comparison to the neighbouring medial entorhinal cortex. Both regions are involved in spatial navigation. Thus, our findings are of importance for unravelling the underlying circuitry of this process and for determining the role of the parasubiculum within this network

Cannabinoid type 2 receptors mediate a cell type-specific self-inhibition in cortical neurons

Endogenous cannabinoids are diffusible lipid ligands of the main cannabinoid receptors type 1 and 2 (CB(1)R and CB(2)R). In the central nervous system endocannabinoids are produced in an activity-dependent manner and have been identified as retrograde modulators of synaptic transmission. Additionally, some neurons display a cell-autonomous slow self-inhibition (SSI) mediated by endocannabinoids. In these neurons, repetitive action potential firing triggers the production of endocannabinoids, which induce a long-lasting hyperpolarization of the membrane potential, rendering the cells less excitable. Different endocannabinoid receptors and effector mechanisms have been described underlying SSI in different cell types and brain areas. Here, we investigate SSI in neurons of layer 2/3 in the somatosensory cortex. High-frequency bursts of action potentials induced SSI in pyramidal cells (PC) and regular spiking non-pyramidal cells (RSNPC), but not in fast-spiking interneurons (FS). In RSNPCs the hyperpolarization was accompanied by a change in input resistance due to the activation of G protein-coupled inward-rectifying K(+) (GIRK) channels. A CB(2)R-specific agonist induced the long-lasting hyperpolarization, whereas preincubation with a CB(2)R-specific inverse agonist suppressed SSI. Additionally, using cannabinoid receptor knockout mice, we found that SSI was still intact in CB(1)R-deficient but abolished in CB(2)R-deficient mice. Taken together, we describe an additional SSI mechanism in which the activity-induced release of endocannabinoids activates GIRK channels via CB(2)Rs. These findings expand our knowledge about cell type-specific differential neuronal cannabinoid receptor signaling and suggest CB(2)R-selective compounds as potential therapeutic approaches