Neuroscience
-
To be highly reliable, synaptic transmission needs postsynaptic receptors (Rs) in precise apposition to the presynaptic release sites. At inhibitory synapses, the postsynaptic protein gephyrin self-assembles to form a scaffold that anchors glycine and GABAARs to the cytoskeleton, thus ensuring the accurate accumulation of postsynaptic receptors at the right place. This protein undergoes several post-translational modifications which control protein-protein interaction and downstream signaling pathways. ⋯ In addition, we will focus on the impact of gephyrin structure and distribution at the nanoscale level on the functional properties of inhibitory synapses as well as the implications of this scaffold protein in synaptic plasticity processes. Finally, we will emphasize how gephyrin genetic mutations or alterations in protein expression levels are implicated in several neuropathological disorders, including autism spectrum disorders, schizophrenia, temporal lobe epilepsy and Alzheimer's disease, all associated with severe deficits of GABAergic signaling. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
-
In the CNS, chemokines and chemokine receptors are involved in pleiotropic physiological and pathological activities. Several evidences demonstrated that chemokine signaling in the CNS plays key homeostatic roles and, being expressed on neurons, glia and endothelial cells, chemokines mediate the bidirectional cross-talk among parenchymal cells. ⋯ In this review we summarize the evidence that chemokines (CXCL12, CX3CL1, CXCL16 and CCL2) modulate neuroprotective processes upon different noxious stimuli and participate to orchestrate neurons-microglia-astrocytes action to preserve and limit brain damage. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
-
Myasthenia gravis (MG) is a relatively rare neurological disease that is usually associated with antibodies to the acetylcholine receptor (AChR). These antibodies (Abs) cause loss of the AChRs from the neuromuscular junction (NMJ), resulting in muscle weakness that can be life-threatening. Another form of the disease is caused by antibodies to muscle specific kinase (MuSK) that result in impaired AChR clustering and numbers at the NMJ, and may also interfere with presynaptic adaptive mechanisms. ⋯ All four conditions can be diagnosed by specific clinical features, electromyography and serum antibody tests, and can be treated effectively by a combination of pharmacological approaches and procedures that reduce the levels of the IgG antibodies. They form the first of a spectrum of diseases in which serum autoantibodies bind to extracellular domains of neuronal proteins throughout the nervous system and lead to constellations of clinical features including paralysis, sensory disturbance and pain, memory loss, seizures, psychiatric disturbance and movement disorders. This review will briefly summarize the ways in which this field has developed, since the 1970s when considerable contributions were made in Ricardo Miledi's laboratory at UCL.
-
The striatal cholinergic system is key in detecting changes in instrumental contingencies. While recent evidence supports this vision, cell type-specific online control on the activity of the cholinergic striatal neurons is necessary to empirically test it. ⋯ Remarkably, a manipulation that perturbs the activity of CINs, rather than inhibiting them also impaired the encoding of the change in contingency. These results emphasize that beyond an increase in the activity of CINs, the intact activity of these cells is required for the identification of an instrumental contingency change.