Somatostatin, a Presynaptic Modulator of Glutamatergic Signal in the Central Nervous System.

Somatostatin is widely diffused in the central nervous system, where it participates to control the efficiency of synaptic transmission. This peptide mainly colocalizes with GABA, in inhibitory, GABA-containing interneurons from which it is actively released in a Ca2+ dependent manner upon application of depolarizing stimuli. Once released in the synaptic cleft, somatostatin acts locally, or it diffuses in the extracellular space through "volume diffusion", a mechanism(s) of distribution which mainly operates in the cerebrospinal fluid and that assures the progression of neuronal signalling from signal-secreting sender structures towards receptor-expressing targeted neurons located extrasynaptically, in a non-synaptic, inter-neuronal form of communication. Somatostatin controls the efficiency of central glutamate transmission by either modulating presynaptically the glutamate exocytosis or by metamodulating the activity of glutamate receptors colocalized and functionally coupled with somatostatin receptors in selected subpopulations of nerve terminals. Deciphering the role of somatostatin in the mechanisms of "volume diffusion" and in the "receptor-receptor interaction" unveils new perspectives in the central role of this fine tuner of synaptic strength, paving the road to new therapeutic approaches for the cure of central disorders.

Modulator-Gated, SUMOylation-Mediated, Activity-Dependent Regulation of Ionic Current Densities Contributes to Short-Term Activity Homeostasis.

Neurons operate within defined activity limits, and feedback control mechanisms dynamically tune ionic currents to maintain this optimal range. This study describes a novel, rapid feedback mechanism that uses SUMOylation to continuously adjust ionic current densities according to changes in activity. Small ubiquitin-like modifier (SUMO) is a peptide that can be post-translationally conjugated to ion channels to influence their surface expression and biophysical properties. Neuronal activity can regulate the extent of protein SUMOylation. This study on the single, unambiguously identifiable lateral pyloric neuron (LP), a component of the pyloric network in the stomatogastric nervous system of male and female spiny lobsters (Panulirus interruptus), focused on dynamic SUMOylation in the context of activity homeostasis. There were four major findings: First, neuronal activity adjusted the balance between SUMO conjugation and deconjugation to continuously and bidirectionally fine-tune the densities of two opposing conductances: the hyperpolarization activated current (Ih) and the transient potassium current (IA). Second, tonic 5 nm dopamine (DA) gated activity-dependent SUMOylation to permit and prevent activity-dependent regulation of Ih and IA, respectively. Third, DA-gated, activity-dependent SUMOylation contributed to a feedback mechanism that restored the timing and duration of LP activity during prolonged modulation by 5 µm DA, which initially altered these and other activity features. Fourth, DA modulatory and metamoduatory (gating) effects were tailored to simultaneously alter and stabilize neuronal output. Our findings suggest that modulatory tone may select a subset of rapid activity-dependent mechanisms from a larger menu to achieve homeostasis under varying conditions.SIGNIFICANCE STATEMENT Post-translational SUMOylation of ion channel subunits controls their interactions. When subunit SUMOylation is dysregulated, conductance densities mediated by the channels are distorted, leading to nervous system disorders, such as seizures and chronic pain. Regulation of ion channel SUMOylation is poorly understood. This study demonstrated that neuronal activity can regulate SUMOylation to reconfigure ionic current densities over minutes, and this regulation was gated by tonic nanomolar dopamine. Dynamic SUMOylation was necessary to maintain specific aspects of neuronal output while the neuron was being modulated by high (5 µm) concentrations of dopamine, suggesting that the gating function may ensure neuronal homeostasis during extrinsic modulation of a circuit.

Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D1-like dopamine receptor signaling.

Astrocytes modulate many neuronal networks, including spinal networks responsible for the generation of locomotor behavior. Astrocytic modulation of spinal motor circuits involves release of ATP from astrocytes, hydrolysis of ATP to adenosine, and subsequent activation of neuronal A1 adenosine receptors (A1Rs). The net effect of this pathway is a reduction in the frequency of locomotor-related activity. Recently, it was proposed that A1Rs modulate burst frequency by blocking the D1-like dopamine receptor (D1LR) signaling pathway; however, adenosine also modulates ventral horn circuits by dopamine-independent pathways. Here, we demonstrate that adenosine produced upon astrocytic stimulation modulates locomotor-related activity by counteracting the excitatory effects of D1LR signaling and does not act by previously described dopamine-independent pathways. In spinal cord preparations from postnatal mice, a D1LR agonist, SKF 38393, increased the frequency of locomotor-related bursting induced by 5-hydroxytryptamine and N-methyl-d-aspartate. Bath-applied adenosine reduced burst frequency only in the presence of SKF 38393, as did adenosine produced after activation of protease-activated receptor-1 to stimulate astrocytes. Furthermore, the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine enhanced burst frequency only in the presence of SKF 38393, indicating that endogenous adenosine produced by astrocytes during network activity also acts by modulating D1LR signaling. Finally, modulation of bursting by adenosine released upon stimulation of astrocytes was blocked by protein kinase inhibitor-(14-22) amide, a protein kinase A (PKA) inhibitor, consistent with A1R-mediated antagonism of the D1LR/adenylyl cyclase/PKA pathway. Together, these findings support a novel, astrocytic mechanism of metamodulation within the mammalian spinal cord, highlighting the complexity of the molecular interactions that specify motor output. NEW & NOTEWORTHY Astrocytes within the spinal cord produce adenosine during ongoing locomotor-related activity or when experimentally stimulated. Here, we show that adenosine derived from astrocytes acts at A1 receptors to inhibit a pathway by which D1-like receptors enhance the frequency of locomotor-related bursting. These data support a novel form of metamodulation within the mammalian spinal cord, enhancing our understanding of neuron-astrocyte interactions and their importance in shaping network activity.

Metamodulation of presynaptic NMDA receptors: New perspectives for pharmacological interventions.

Metamodulation shifted the scenario of the central neuromodulation from a simplified unimodal model to a multimodal one. It involves different receptors/membrane proteins physically associated or merely colocalized that act in concert to control the neuronal functions influencing each other. Defects or maladaptation of metamodulation would subserve neuropsychiatric disorders or even synaptic adaptations relevant to drug dependence. Therefore, this "vulnerability" represents a main issue to be deeply analyzed to predict its aetiopathogenesis, but also to propose targeted pharmaceutical interventions. The review focusses on presynaptic release-regulating NMDA receptors and on some of the mechanisms of their metamodulation described in the literature. Attention is paid to the interactors, including both ionotropic and metabotropic receptors, transporters and intracellular proteins, which metamodulate their responsiveness in physiological conditions but also undergo adaptation that are relevant to neurological dysfunctions. All these structures are attracting more and more the interest as promising druggable targets for the treatment of NMDA receptor-related central diseases: these substances would not exert on-off control of the colocalized NMDA receptors (as usually observed with NMDA receptor full agonists/antagonists), but rather modulate their functions, with the promise of limiting side effects that would favor their translation from preclinic to clinic. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".

Synaptosomes and Metamodulation of Receptors.

Synaptosomes are re-sealed pinched off nerve terminals that maintain all the main structural and functional features of the original structures and that are appropriate to study presynaptic events. Because of the discovery of new structural and molecular events that dictate the efficiency of transmitter release and of its receptor-mediated control in the central nervous system, the interest in this tissue preparation is continuously renewing. Most of these events have been already discussed in previous reviews, but few of them were not and deserve some comments since they could suggest new functional and possibly therapeutic considerations. Among them, the "metamodulation" of receptors represents an emerging aspect that dramatically increased the complexity of the presynaptic compartment, adding new insights to the role of presynaptic receptors as modulators of chemical synapses. Deciphering the mechanism of presynaptic metamodulation would permit indirect approaches to control the activity of presynaptic release-regulating receptors that are currently orphans of direct ligands/modulators, paving the road for the proposal of new therapeutic approaches for central neurological diseases.

Activation of high and low affinity dopamine receptors generates a closed loop that maintains a conductance ratio and its activity correlate.

Neuromodulators alter network output and have the potential to destabilize a circuit. The mechanisms maintaining stability in the face of neuromodulation are not well described. Using the pyloric network in the crustacean stomatogastric nervous system, we show that dopamine (DA) does not simply alter circuit output, but activates a closed loop in which DA-induced alterations in circuit output consequently drive a change in an ionic conductance to preserve a conductance ratio and its activity correlate. DA acted at low affinity type 1 receptors (D1Rs) to induce an immediate modulatory decrease in the transient potassium current (IA) of a pyloric neuron. This, in turn, advanced the activity phase of that component neuron, which disrupted its network function and thereby destabilized the circuit. DA simultaneously acted at high affinity D1Rs on the same neuron to confer activity-dependence upon the hyperpolarization activated current (Ih) such that the DA-induced changes in activity subsequently reduced Ih. This DA-enabled, activity-dependent, intrinsic plasticity exactly compensated for the modulatory decrease in IA to restore the IA:Ih ratio and neuronal activity phase, thereby closing an open loop created by the modulator. Activation of closed loops to preserve conductance ratios may represent a fundamental operating principle neuromodulatory systems use to ensure stability in their target networks.

Tuning and fine-tuning of synapses with adenosine.

The 'omnipresence' of adenosine in all nervous system cells (neurons and glia) together with the intensive release of adenosine following insults, makes adenosine as a sort of 'maestro' of synapses leading to the homeostatic coordination of brain function. Besides direct actions of adenosine on the neurosecretory mechanisms, where adenosine operates to tune neurotransmitter release, receptor-receptor interactions as well as interplays between adenosine receptors and transporters occur as part of the adenosine's attempt to fine tuning synaptic transmission. This review will focus on the different ways adenosine can use to trigger or brake the action of several neurotransmitters and neuromodulators. Adenosine receptors cross talk with other G protein coupled receptors (GPCRs), with ionotropic receptors and with receptor kinases. Most of these interactions occur through A2A receptors, which in spite their low density in some brain areas, such as the hippocampus, may function as metamodulators. Tonic adenosine A2A receptor activity is a required step to allow synaptic actions of neurotrophic factors, namely upon synaptic transmission at both pre- and post-synaptic level as well as upon synaptic plasticity and neuronal survival. The implications of these interactions in normal brain functioning and in neurologic and psychiatric dysfunction will be discussed.