Elevated serum levels of methylglyoxal are associated with impaired liver function in patients with liver cirrhosis

Methylglyoxal (MGO) is a highly reactive dicarbonyl species that forms advanced glycation end products (AGEs). The binding of these AGEs to their receptor (RAGE) causes and sustains severe inflammation. Systemic inflammation is postulated to be a major driver in the progression of liver cirrhosis. However, the role of circulating MGO levels in liver cirrhosis remains unknown. In this study, we investigated the serum levels of two dicarbonyl species, MGO and glyoxal (GO) using tandem mass spectrometry (HPLC–MS/MS) and evaluated their association with disease severity. A total of 51 inpatients and outpatients with liver cirrhosis of mixed etiology and different disease stages were included. Elevated MGO levels were seen in an advanced stage of liver cirrhosis (p < 0.001). High MGO levels remained independently associated with impaired liver function, as assessed by the model for end-stage liver disease (MELD) (β = 0.448, p = 0.002) and acute decompensation (AD) (β = 0.345, p = 0.005) scores. Furthermore, MGO was positively correlated with markers of systemic inflammation (IL-6, p = 0.004) and the development of ascites (p = 0.013). In contrast, no changes were seen in GO serum levels. Circulating levels of MGO are elevated in advanced stages of liver cirrhosis and are associated with impaired liver function and liver-related parameters

Ih Tunes Theta/Gamma Oscillations and Cross-Frequency Coupling In an In Silico CA3 Model

channels are uniquely positioned to act as neuromodulatory control points for tuning hippocampal theta (4–12 Hz) and gamma (25 Hz) oscillations, oscillations which are thought to have importance for organization of information flow. contributes to neuronal membrane resonance and resting membrane potential, and is modulated by second messengers. We investigated oscillatory control using a multiscale computer model of hippocampal CA3, where each cell class (pyramidal, basket, and oriens-lacunosum moleculare cells), contained type-appropriate isoforms of . Our model demonstrated that modulation of pyramidal and basket allows tuning theta and gamma oscillation frequency and amplitude. Pyramidal also controlled cross-frequency coupling (CFC) and allowed shifting gamma generation towards particular phases of the theta cycle, effected via \u27s ability to set pyramidal excitability. Our model predicts that in vivo neuromodulatory control of allows flexibly controlling CFC and the timing of gamma discharges at particular theta phases

Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell - motor neuron circuit

Enjin A, Perry S, Hilscher MM, Nagaraja C, Larhammar M, Gezelius H, Eriksson A, Leão KE, Kullander K (2017) Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell - motor neuron circuit. J Neurosci. May 8. pii: 0949-16. doi: 10.1523/JNEUROSCI.0949-16.2017.When activating muscles, motor neurons in the spinal cord also activate Renshaw cells, which provide recurrent inhibitory feedback to the motor neurons. The tight coupling with motor neurons suggests that Renshaw cells have an integral role in movement, a role that is yet to be elucidated. Here we used the selective expression of the nicotinic cholinergic receptor alpha 2 (Chrna2) in mice to genetically target the vesicular inhibitory amino acid transporter (VIAAT) in Renshaw cells. Loss of VIAAT from Chrna2Cre expressing Renshaw cells did not impact any aspect of drug-induced fictive locomotion in the neonatal mouse, nor did it change gait, motor coordination or grip strength in adult mice of both sexes. However, motor neurons from neonatal mice lacking VIAAT in Renshaw cells received spontaneous inhibitory synaptic input with a reduced frequency, showed lower input resistance and had an increased number of proprioceptive glutamatergic and calbindin labeled putative Renshaw cell synapses on their soma and proximal dendrites. Concomitantly, Renshaw cells developed with increased excitability and a normal number of cholinergic motor neuron synapses indicating a compensatory mechanism within the recurrent inhibitory feedback circuit. Our data suggest an integral role for Renshaw cell signaling in shaping the excitability and synaptic input to motor neurons

Direct reprogramming of adult human somatic stem cells into functional neurons using Sox2, Ascl1, and Neurog2

Reprogramming of somatic cells into induced pluripotent stem cells (iPS) or directly into cells from a different lineage, including neurons, has revolutionized research in regenerative medicine in recent years. Mesenchymal stem cells are good candidates for lineage reprogramming and autologous transplantation, since they can be easily isolated from accessible sources in adult humans, such as bone marrow and dental tissues. Here, we demonstrate that expression of the transcription factors (TFs) SRY (sex determining region Y)-box 2 (Sox2), Mammalian achaete-scute homolog 1 (Ascl1), or Neurogenin 2 (Neurog2) is sufficient for reprogramming human umbilical cord mesenchymal stem cells (hUCMSC) into induced neurons (iNs). Furthermore, the combination of Sox2/Ascl1 or Sox2/Neurog2 is sufficient to reprogram up to 50% of transfected hUCMSCs into iNs showing electrical properties of mature neurons and establishing synaptic contacts with co-culture primary neurons. Finally, we show evidence supporting the notion that different combinations of TFs (Sox2/Ascl1 and Sox2/Neurog2) may induce multiple and overlapping neuronal phenotypes in lineage-reprogrammed iNs, suggesting that neuronal fate is determined by a combination of signals involving the TFs used for reprogramming but also the internal state of the converted cell. Altogether, the data presented here contribute to the advancement of techniques aiming at obtaining specific neuronal phenotypes from lineage-converted human somatic cells to treat neurological disorders

Synchronisation through nonreciprocal connections in a hybrid hippocampus microcircuit

Synchronisation among neurons is thought to arise from the interplay between excitation and inhibition; however, the connectivity rules that contribute to synchronisation are still unknown. We studied these issues in hippocampal CA1 microcircuits using paired patch clamp recordings and real time computing. By virtually connecting a model interneuron with two pyramidal cells (PCs), we were able to test the importance of connectivity in synchronising pyramidal cell activity. Our results show that a circuit with a nonreciprocal connection between pyramidal cells and no feedback from PCs to the virtual interneuron produced the greatest level of synchronisation and mutual information between PC spiking activity. Moreover, we investigated the role of intrinsic membrane properties contributing to synchronisation where the application of a specific ion channel blocker, ZD7288 dramatically impaired PC synchronisation. Additionally, background synaptic activity, in particular arising from NMDA receptors, has a large impact on the synchrony observed in the aforementioned circuit. Our results gives new insights to the basic connection paradigms of microcircuits that lead to coordination and the formation of assemblies

The alpha2 nicotinic acetylcholine receptor, a subunit with unique and selective expression in inhibitory interneurons associated with principal cells

Nicotinic acetylcholine receptors (nAChRs) play crucial roles in various human disorders, with the alpha 7, alpha 4, alpha 6, and alpha 3-containing nAChR subtypes extensively studied in relation to conditions such as Alzheimer's disease, Parkinson's disease, nicotine dependence, mood disorders, and stress disorders. In contrast, the alpha 2-nAChR subunit has received less attention due to its more restricted expression and the scarcity of specific agonists and antagonists for studying its function. Nevertheless, recent research has shed light on the unique expression pattern of the Chrna2 gene, which encodes the alpha 2-nAChR subunit, and its involvement in distinct populations of inhibitory interneurons. This review highlights the structure, pharmacology, localization, function, and disease associations of alpha 2-containing nAChRs and points to the unique expression pattern of the Chrna2 gene and its role in different inhibitory interneuron populations. These populations, including the oriens lacunosum moleculare (OLM) cells in the hippocampus, Martinotti cells in the neocortex, and Renshaw cells in the spinal cord, share common features and contribute to recurrent inhibitory microcircuits. Thus, the alpha 2-nAChR subunit's unique expression pattern in specific interneuron populations and its role in recurrent inhibitory microcircuits highlight its importance in various physiological processes. Further research is necessary to uncover the comprehensive functionality of alpha 2-containing nAChRs, delineate their specific contributions to neuronal circuits, and investigate their potential as therapeutic targets for related disorders

Control of phasic firing by a background leak current in avian forebrain auditory neurons

Central neurons express a variety of neuronal types and ion channels that promote firing heterogeneity among their distinct neuronal populations. Action potential (AP) phasic firing, produced by low-threshold voltage activated potassium currents (VAKCs), is commonly observed in mammalian brainstem neurons involved in the processing of temporal properties of the acoustic information. The avian caudomedial nidopallium (NCM) is an auditory area analogous to portions of the mammalian auditory cortex that is involved in the perceptual discrimination and memorization of birdsong and shows complex responses to auditory stimuli We performed in vitro whole-cell patch-clamp recordings in brain slices from adult zebra finches (Taeniopygia guttata) and observed that half of NCM neurons fire APs phasically in response to membrane depolarizations, while the rest fire transiently or tonically. Phasic neurons fired APs faster and with more temporal precision than tonic and transient neurons. These neurons had similar membrane resting potentials, but phasic neurons had lower membrane input resistance and time constant. Surprisingly phasic neurons did not express low-threshold VAKCs, which curtailed firing in phasic mammalian brainstem neurons, having similar VAKCs than the other NCM neurons. The phasic firing was determined not by VAKCs, but by the potassium background leak conductances, which was more prominently expressed in phasic neurons, a result corroborated by pharmacological, dynamic-clamp and modeling experiments. These results reveal a new role for leak currents in generating firing diversity in central neurons

Novel markers for OLM interneurons in the hippocampus

Oriens-lacunosum moleculare (OLM) cells are a major subclass of hippocampal interneurons involved in controlling synaptic plasticity in Shaffer collateral synapses (Leão et al., 2012) and electrogenesis in pyramidal cell (PC) dendrites (Lovett-Barron et al., 2012). Their firing phase is locked with theta oscillations, which imply a role for these cells in theta rhythmogenesis (Klausberger and Somogyi, 2008; Forro et al., 2015). OLM interneurons also appear to be key in the pathophysiology of epilepsy (Dugladze et al., 2007) and is the most vulnerable interneuron population in models of epilepsy (Dinocourt et al., 2003). Somatostatin has been frequently used as a molecular marker for identification of OLM cells (Forro et al., 2015). Two recent studies suggest that the OLM cell population is heterogeneous. First, the expression of cholinergic receptor, nicotinic, alpha polypeptide 2 (Chrna2) seems to be restricted to OLM interneurons neurons of CA1 (Leão et al., 2012). Second, a subset of OLM interneurons that expresses the 5HT3a receptor is derived from the caudal ganglionic eminence and do not entrain to gamma oscillations. In contrast, OLM interneurons derived from the medial ganglionic eminence partially phase lock to in vitro gamma oscillations and do not express 5HT3a receptors (Chittajallu et al., 2013). Further, other dendritic targeting interneurons in the hippocampus also express somatostatin (Lovett-Barron et al., 2014). Hence, functional studies of OLM cell in hippocampal function have been targeting a relatively heterogenous cell population