Morphological plasticity of astroglia: Understanding synaptic microenvironment

Memory formation in the brain is thought to rely on the remodeling of synaptic connections which eventually results in neural network rewiring. This remodeling is likely to involve ultrathin astroglial protrusions which often occur in the immediate vicinity of excitatory synapses. The phenomenology, cellular mechanisms, and causal relationships of such astroglial restructuring remain, however, poorly understood. This is in large part because monitoring and probing of the underpinning molecular machinery on the scale of nanoscopic astroglial compartments remains a challenge. Here we briefly summarize the current knowledge regarding the cellular organisation of astroglia in the synaptic microenvironment and discuss molecular mechanisms potentially involved in use-dependent astroglial morphogenesis. We also discuss recent observations concerning morphological astroglial plasticity, the respective monitoring methods, and some of the newly emerging techniques that might help with conceptual advances in the area. GLIA 2015

On the G-protein-coupled receptor heteromers and their allosteric receptor-receptor interactions in the central nervous system: focus on their role in pain modulation

The modulatory role of allosteric receptor-receptor interactions in the pain pathways of the Central Nervous System and the peripheral nociceptors has become of increasing interest. As integrators of nociceptive and antinociceptive wiring and volume transmission signals, with a major role for the opioid receptor heteromers, they likely have an important role in the pain circuits and may be involved in acupuncture. The delta opioid receptor (DOR) exerts an antagonistic allosteric influence on the mu opioid receptor (MOR) function in a MOR-DOR heteromer. This heteromer contributes to morphine-induced tolerance and dependence, since it becomes abundant and develops a reduced G-protein-coupling with reduced signaling mainly operating via beta-arrestin 2 upon chronic morphine treatment. A DOR antagonist causes a return of the Gi/o binding and coupling to the heteromer and the biological actions of morphine. The gender- and ovarian steroid-dependent recruitment of spinal cord MOR/kappa opioid receptor (KOR) heterodimers enhances antinociceptive functions and if impaired could contribute to chronic pain states in women. MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, mediating morphine induced itch. Other mechanism for the antinociceptive actions of acupuncture along meridians may be that it enhances the cross-desensitization of the TRPA1 (chemical nociceptor)-TRPV1 (capsaicin receptor) heteromeric channel complexes within the nociceptor terminals located along these meridians. Selective ionotropic cannabinoids may also produce cross-desensitization of the TRPA1-TRPV1 heteromeric nociceptor channels by being negative allosteric modulators of these channels leading to antinociception and antihyperalgesia

The Paradox of Astroglial Ca2+ Signals at the Interface of Excitation and Inhibition

Astroglial networks constitute a non-neuronal communication system in the brain and are acknowledged modulators of synaptic plasticity. A sophisticated set of transmitter receptors in combination with distinct secretion mechanisms enables astrocytes to sense and modulate synaptic transmission. This integrative function evolved around intracellular Ca2+ signals, by and large considered as the main indicator of astrocyte activity. Regular brain physiology meticulously relies on the constant reciprocity of excitation and inhibition (E/I). Astrocytes are metabolically, physically, and functionally associated to the E/I convergence. Metabolically, astrocytes provide glutamine, the precursor of both major neurotransmitters governing E/I in the central nervous system (CNS): glutamate and γ-aminobutyric acid (GABA). Perisynaptic astroglial processes are structurally and functionally associated with the respective circuits throughout the CNS. Astonishingly, in astrocytes, glutamatergic as well as GABAergic inputs elicit similar rises in intracellular Ca2+ that in turn can trigger the release of glutamate and GABA as well. Paradoxically, as gliotransmitters, these two molecules can thus strengthen, weaken or even reverse the input signal. Therefore, the net impact on neuronal network function is often convoluted and cannot be simply predicted by the nature of the stimulus itself. In this review, we highlight the ambiguity of astrocytes on discriminating and affecting synaptic activity in physiological and pathological state. Indeed, aberrant astroglial Ca2+ signaling is a key aspect of pathological conditions exhibiting compromised network excitability, such as epilepsy. Here, we gather recent evidence on the complexity of astroglial Ca2+ signals in health and disease, challenging the traditional, neuro-centric concept of segregating E/I, in favor of a non-binary, mutually dependent perspective on glutamatergic and GABAergic transmission

Studies of intercellular Ca2+ signaling and gap-junction coupling in the developing cochlea of mouse models affected by congenital hearing loss

Connexin 26 (Cx26) and connexin 30 (Cx30) form gap junction channels that allow the intercellular diffusion of the Ca2+ mobilizing second messenger IP3. They also form hemichannels that release ATP from the endolymphatic surface of cochlear supporting and epithelial cells. Released ATP in turn activates G-protein coupled P2Y2 and P2Y4 receptors, PLC-dependent generation of IP3, release of Ca2+ from intracellular stores, permitting the regenerative propagation of intercellular Ca2+ signals. In the course of this work, we found that cochlear non-sensory cells of the greater and lesser epithelial ridge (GER and LER, respectively) share the same PLC- and IP3R-dependent signal transduction cascade activated by ATP. In addition, we demonstrated that ATP-dependent Ca2+ signaling activity in cochlear non-sensory cells is spatially graded from the apex to the base of the cochlea during the first postnatal week. Ca2+ signaling under these conditions depends on inositol-1,4,5-trisphosphate generation from phospholipase C (PLC)-dependent hydrolysis of PI(4,5)P(2). Thus we analyzed mice with defective expression of PIPKIγ and found that (i) this enzyme is essential for the acquisition of hearing; (ii) it is primarily responsible for the synthesis of the receptor-regulated PLC-sensitive PI(4,5)P(2) pool in the cell syncytia that supports auditory hair cells and; (iii) spatially graded impairment of the PIP2-IP3-Ca2+ signaling pathway in cochlear non-sensory cells affects the level of gap junction coupling. Vice versa, we found defective gap junction coupling and intercellular IP3-dependent Ca2+ signaling the cochlea of mice with targeted ablation Cx26 or Cx30, as well as in mice knock in for a point mutation (Cx30T5M) associated with human congenital deafness. Altogether, our findings link bidirectionally defective hearing acquisition to Ca2+ signaling impairment and decreased biochemical coupling in the developing cochlea. Transduction of connexin deficient cochlear cultures with a bovine adeno associated virus vectors encoding Cx26 or Cx30 restored protein expression, rescued both gap junction coupling and Ca2+ signaling. Based on this work, we conclude that in vivo connexin gene delivery to the inner ear is a route worth exploring to rescue hearing function in mouse models of deafness and, in future, may lead to the development of therapeutic interventions in humans