Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.

A synaptic model of memory: long-term potentiation in the hippocampus

The distinct protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - soluble oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insoluble deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which amyloid beta-protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.

Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.

### A. Overview

Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface receptors termed purine receptors. In this review particular emphasis is placed on the discrepancy between the

/pdf/receptors-for-purines-and-pyrimidines-56f78tnpew.pdf

Receptors for Purines and Pyrimidines

The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this

/pdf/the-glutamate-receptor-ion-channels-560mntczdb.pdf

The glutamate receptor ion channels

LTP and LTD: an embarrassment of riches.

ATP is a key extracellular messenger that mediates the propagation of Ca 2 + waves in astrocyte networks in various regions of the CNS. ATP-mediated Ca 2 + signals play critical roles in astrocyte proliferation and differentiation and in modulating neuronal activity. The actions of ATP on astrocytes are via two distinct subtypes of P2Y purinoceptors, P2Y 1 and P2Y 2 receptors (P2Y 1 Rs and P2Y 2 Rs), G-protein coupled receptors that stimulate mobilization of intracellular Ca 2 + ([Ca 2 + ] i ) via the phospholipase Cβ-IP 3 pathway. We report here that P2Y 1 R-mediated and P2Y 2 R-mediated Ca 2 + responses differentially show two forms of activity-dependent negative feedback. First, Ca 2 + responses mediated by either receptor exhibit slow depression that is independent of stimulation frequency. Second, responses mediated by P2Y 1 Rs, but not those mediated by P2Y 2 Rs, show rapid oscillations after high-frequency stimulation. We demonstrate that the oscillations are mediated by recruiting negative feedback by protein kinase C, and we map the site responsible for the effect of protein kinase C to Thr 339 in the C terminus of P2Y 1 R. We propose that frequency-dependent changes in ATP-mediated Ca 2 + signaling pathways may modulate astrocyte function and astrocyte–neuron signaling in the CNS.

https://www.jneurosci.org/content/jneuro/23/11/4437.full.pdf

Differential Frequency Dependence of P2Y1- and P2Y2- Mediated Ca 2+ Signaling in Astrocytes

MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells.

NMDA receptors are movin' in

Nociceptive inputs from primary afferents are primarily mediated at fast glutamatergic synapses onto second order neurons in the dorsal horn of the spinal cord through activation of AMPA/kainate and NMDA receptor subtypes of ionotropic glutamate receptors. At these glutamatergic synapses several forms of short-lasting and long-lasting enhancement of synaptic transmission are known. Enhancement of excitatory synaptic transmission in nociceptive pathways is thought to be a key neural substrate underlying chronic pain, and thus the cellular and molecular mechanisms producing this enhancement represent potential targets for developing novel forms of therapeutics. Central to the mechanisms for pain hypersensitivity is the NMDA receptor, the activity of which is facilitated by convergent intracellular biochemical cascades in dorsal horn neurons. Cellular changes are not restricted to neurons in the dorsal horn, however, and there is growing evidence for involvement of glia, and of glia-neuronal signaling, in initiating and sustaining enhancement of nociceptive transmission. In particular, a role has emerged for microglia in pain hypersensitivity following nerve injury. This expanded understanding of cellular and molecular signalling mechanisms in the dorsal horn, that includes both neurons and glia, provides a basis of creating new types of strategies for management, and also for diagnosis, of chronic pain.

Cellular signalling pathways of spinal pain neuroplasticity as targets for analgesic development.

Diurnal variations in pain hypersensitivity are common in chronic pain disorders, but the underlying mechanisms are enigmatic. Here, we report that mechanical pain hypersensitivity in sciatic nerve-injured mice shows pronounced diurnal alterations, which critically depend on diurnal variations in glucocorticoids from the adrenal glands. Diurnal enhancement of pain hypersensitivity is mediated by glucocorticoid-induced enhancement of the extracellular release of ATP in the spinal cord, which stimulates purinergic receptors on microglia in the dorsal horn. We identify serum- and glucocorticoid-inducible kinase-1 (SGK-1) as the key molecule responsible for the glucocorticoid-enhanced release of ATP from astrocytes. SGK-1 protein levels in spinal astrocytes are increased in response to glucocorticoid stimuli and enhanced ATP release by opening the pannexin-1 hemichannels. Our findings reveal an unappreciated circadian machinery affecting pain hypersensitivity caused by peripheral nerve injury, thus opening up novel approaches to the management of chronic pain.

Michael W. Salter

Papers

Differential Frequency Dependence of P2Y1- and P2Y2- Mediated Ca 2+ Signaling in Astrocytes

MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells.

NMDA receptors are movin' in

Cellular signalling pathways of spinal pain neuroplasticity as targets for analgesic development.

Glucocorticoid regulation of ATP release from spinal astrocytes underlies diurnal exacerbation of neuropathic mechanical allodynia.