Lack of sigma-1 receptor exacerbates ALS progression in mice.

The function of the sigma-1 receptor (S1R) has been implicated in modulating the activity of various ion channels. In the CNS S1R is enriched in cholinergic postsynaptic densities in spinal cord motoneurons (MNs). Mutations in S1R have been found in familial cases of amyotrophic lateral sclerosis (ALS). In this study we show that a knockout of S1R in the SOD1*G93A mouse model of ALS significantly reduces longevity (end stage). Electrophysiological experiments demonstrate that MN of mice lacking S1R exhibit increased excitability. Taken together the data suggest the S1R acts as a brake on excitability, an effect that might enhance longevity in an ALS mouse model.

Development of the sigma-1 receptor in C-terminals of motoneurons and colocalization with the N,N'-dimethyltryptamine forming enzyme, indole-N-methyl transferase.

The function of the sigma-1 receptor (S1R) has been linked to modulating the activities of ion channels and G-protein-coupled receptors (GPCR). In the CNS, the S1R is expressed ubiquitously but is enriched in mouse motoneurons (MN), where it is localized to subsurface cisternae of cholinergic postsynaptic densities, also known as C-terminals. We found that S1R is enriched in mouse spinal MN at late stages of embryonic development when it is first visualized in the endoplasmic reticulum. S1Rs appear to concentrate at C-terminals of mouse MN only on the second week of postnatal development. We found that indole-N-methyl transferase (INMT), an enzyme that converts tryptamine into the sigma-1 ligand dimethyltryptamine (DMT), is also localized to postsynaptic sites of C-terminals in close proximity to the S1R. This close association of INMT and S1Rs suggest that DMT is synthesized locally to effectively activate S1R in MN.

The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral study.

The sigma-1 receptor regulates various ion channel activity and possesses protein chaperone function. Using an antibody against the full sequence of the sigma-1 receptor we detected immunostaining in wild type but not in knockout mice. The receptor was found primarily in motoneurons localized to the brainstem and spinal cord. At the subcellular level the receptor is restricted to large cholinergic postsynaptic densities on the soma of motoneurons and is colocalized with the Kv2.1 potassium channel and the muscarinic type 2 cholinergic receptor. Ultrastructural analysis of the neurons indicates that the immunostained receptor is located close but separate from the plasma membrane, possibly in subsurface cisternae formed from the endoplasmic reticulum (ER), which are a prominent feature of cholinergic postsynaptic densities. Behavioral testing on a rotorod revealed that Sigma-1 receptor knockout mice remained on the rotorod for significantly less time (a shorter latency period) compared to the wild type mice. Together these data indicate that the sigma-1 receptor may play a role in the regulation of motor behavior.

Distribution of calcium ions in the mixed synapses of Mauthner neurons in the goldfish in normal conditions, in exhaustion, and in conditions of adaptation to exhaustion.

The aim of this study was to investigate the structure of large myelinated club terminals of Mauthner neurons (MN) in the goldfish at different levels of functional activity and the distribution within these synapses of calcium ions as assessed using a modified pyroantimonate method. In intact preparations, calcium pyroantimonate precipitates were not seen in gap junctions (GJ) or desmosome-like contacts (DLC). Fibrillar bridges in DLC clefts were not contrasted. After natural stimulation, which induces long-term adaptation in MN, GJ showed electron-dense precipitates lining the whole cleft. Granules and clumps of precipitate were also seen in DLC clefts, with intense deposition on bridges. Increases in calcium ion concentrations to and above the levels detectable by the pyroantimonate method are known to block electrotonic transmission; filamentous actin is known to conduct the electrotonic signal as a cation current. The staining of DLC bridges with calcium pyroantimonate is therefore evidence for an association between calcium ions and actin molecules, as DLC bridges consist of actin, i.e., we have obtained evidence for the functioning of bridges as electrotonic transsynaptic shunts at the moment of fixation. These data lead to the conclusion that DLC in mixed synapses, apart from the known adhesive functions, also have a communication function. This appears in extreme conditions, allowing the synapse to maintain or change its conductivity according to ongoing need.