Acetylcholine enhances deviance detection in Hodgkin-Huxley neuronal networks.

Amyotrophic lateral sclerosis (ALS) is a degenerative neuromuscular disease characterised by death of motor neurons (MNs) and resultant muscle paralysis. There is currently no cure for ALS with most patients dying of neuromuscular respiratory failure within 2-5 years of diagnosis. 80-90% of ALS cases are sporadic and are usually caused by an interplay of environmental and genetic factors. The remaining cases have known heritable causes, and are predominantly associated with a single dominant mutation in one of ~30 known ALS-linked genes, including chromosome 9 open reading frame 72 (C9orf72), superoxide dismutase 1 (SOD1), transactive response DNA binding protein 43 (TDP-43) and fused in sarcoma (FUS). Several genetic causes and risk factors, including biological sex and age, have been associated with ALS. Moreover, multiple molecular changes have been noted in MNs in ALS models, including oxidative stress, excitotoxicity, neuroinflammation, neuronal hyperexcitation, and axonopathy. Differing explanations have been proposed to explain MN death in ALS. For example, hypotheses commonly labelled “dying forward” and “dying back” propose alternative initiation sites for MN degeneration in ALS. However, both may occur simultaneously or sequentially, and the key mechanism(s) that drive ALS pathology remain elusive. Adding to this complexity, MNs are not uniformly affected in ALS. For example, fast-twitch α-MNs are highly susceptible to cell death, whereas other MNs, such as those in the oculomotor nucleus, remain relatively preserved, even at advanced disease stages. These uncertainties underscore the need to consider not only cell-intrinsic mechanisms but also extracellular influences that may shape MN vulnerability in ALS. Three major extracellular structures make up the extracellular matrix (ECM) of the central nervous system (CNS): the basement membrane, perineuronal nets (PNNs), and the interstitial matrix. PNNs directly surround the cell body, proximal dendrites and axon initial segment of some neurons, including many interneurons and MNs. PNN components are secreted by neurons, oligodendrocytes, microglia, and astrocytes. They consist of a hyaluronan backbone and multiple proteoglycans, including aggrecan, versican, brevican, and other linker proteins, such as tenascin-R. In rats, up to 80% of spinal MNs have PNNs, and 90% of α-MNs are positive for aggrecan. Components of PNNs are liable to degradation by a host of catabolic enzymes, including matrix metalloproteinases (MMPs) and members of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family. Various functions have been associated with PNNs, including protection of neurons against oxidative stress, particularly iron-induced oxidative stress, regulation of memory and plasticity, and control of neuronal excitability. Alterations to PNNs have been reported in a range of neurological diseases such as Alzheimer’s disease, schizophrenia, multiple sclerosis and epilepsy. Several studies have suggested potential links between PNNs and ALS pathology. For example, both TDP-43 Q331K and SOD1 G93A mice show significant reductions in PNNs around α-MNs at disease onset and mid-stage compared to controls. Similarly, transgenic rats harbouring a His46Arg mutation in the SOD1 gene demonstrate progressive loss of PNNs around susceptible MNs in the ventral horns of the lumbar spinal cord. Additional work suggests that PNN components influence excitatory balance, alterations of which are a pathological hallmark of ALS. For example, depletion of hyaluronan synthase 3 (), which is expressed in PNN-bearing MNs in the spinal cord, results in an epileptic phenotype. Excitatory synaptic transmission is also increased in tenascin-R-deficient mice, which also exhibit motor coordination deficits. Other studies have implicated matrix-remodelling enzymes. For example, while MMP9 is expressed by the most vulnerable MNs to cell death in ALS, it is absent in areas that are resistant to disease. Moreover, reducing MMP9 function resulted in SOD1 G93A mice retaining 75% innervation in the normally vulnerable tibialis anterior muscle compared to controls. Evidence in humans is more limited, but post-mortem studies on sporadic ALS patients have identified increases in hyaluronan binding protein 2 and decreases in tenascin-R in their cerebral spinal fluid.