NMDA Receptors in Astrocytes

Astrocytes support glutamatergic neurotransmission in the central nervous system through multiple mechanisms which include: (i) glutamate clearance and control over glutamate spillover due to operation of glutamate transporters; (ii) supply of obligatory glutamate precursor glutamine via operation of glutamate–glutamine shuttle; (iii) supply of l-serine, the indispensable precursor of positive NMDA receptors neuromodulator d-serine and (iv) through overall homoeostatic control of the synaptic cleft. Astroglial cells express an extended complement of ionotropic and metabotropic glutamate receptors, which mediate glutamatergic input to astrocytes. In particular a sub-population of astrocytes in the cortex and in the spinal cord express specific type of NMDA receptors assembled from two GluN1, one GluN2C or D and one GluN3 subunits. This composition underlies low Mg²⁺ sensitivity thus making astroglial NMDA receptors operational at resting membrane potential. These NMDA receptors generate ionic signals in astrocytes and are linked to several astroglial homoeostatic molecular cascades.

     

Astrocytes in endocannabinoid signalling

Astrocytes are emerging as integral functional components of synapses, responding to synaptically released neurotransmitters and regulating synaptic transmission and plasticity. Thus, they functionally interact with neurons establishing tripartite synapses: a functional concept that refers to the existence of communication between astrocytes and neurons and its crucial role in synaptic function. Here, we discuss recent evidence showing that astrocytes are involved in the endocannabinoid (ECB) system, responding to exogenous cannabinoids as well as ECBs through activation of type 1 cannabinoid receptors, which increase intracellular calcium and stimulate the release of glutamate that modulates synaptic transmission and plasticity. We also discuss the consequences of ECB signalling in tripartite synapses on the astrocyte-mediated regulation of synaptic function, which reveal novel properties of synaptic regulation by ECBs, such as the spatially controlled dual effect on synaptic strength and the lateral potentiation of synaptic efficacy. Finally, we discuss the potential implications of ECB signalling for astrocytes in brain pathology and animal behaviour.     

A long-lasting facilitation of hippocampal neurotransmission via a phospholipase A2 signaling pathway.

Phospholipase A2, which is linked to a protein kinase C pathway, hydrolyzes phosphatidylcholine into cis-unsaturated free fatty acids and lysophosphatidylcholine (lysoPC). The present study investigated the effect of the free fatty acids, such as arachidonic, oleic, linoleic, and linolenic acid, and lysoPC on neurotransmission by monitoring population spikes (PSs) from the granular cell layer of rat hippocampal slices. All the free fatty acids and lysoPC examined here gradually increased PS amplitude to a different extent, the effect being evident 60 min after treatment. No significant synergistic enhancement in the PS amplitude was not induced by arachidonic acid following oleic acid, linoleic acid or lysoPC. The results of the present study, thus, demonstrate that phospholipase A2-linked free fatty acids and lysoPC are employed in the sustained facilitation of hippocampal neurotransmission, suggesting a significant role of a phospholipase A2 signaling pathway in the neuroplasticity.     

A unified theory of presynaptic chemical neurotransmission

The mechanism of neurotransmission and its modulation involves the direct role of calcium on membranes, and calcium's ability to activate synergistically and simultaneously a host of interdependent enzymatic cascades in synaptic and coated vesicles and the presynaptic plasma membrane. Enzymatic products formed can either amplify or depress synaptic vesicle exocytosis and synaptic vesicle regeneration via the coated pit/vesicle system. Rate amplification produced by a series of parallel, multistepped, interconnected enzymatic cascades as well as the optimal geometric spatial orientation of synaptic vesicles induced by presynaptic structures is hypothesized to explain how neurotransmitter is released within 200 musec upon calcium entry into the axon terminal.     

Glutamatergic neurotransmission in alcoholism

Substance abuse and dependence is the most common psychiatric problem. Alcohol is the most commonly abused substance and most people who abuse other substance(s) abuse alcohol at the same time. Accumulating evidence suggests that neurophysiological and pathological effects of ethanol are mediated to a considerable extent via the glutamatergic system. Ethanol disrupts glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor and by promoting neuronal toxicity through upregulation of the NMDA receptor density. Therefore, short-term/acute ethanol treatment results in a blockade of NMDA receptor-mediated neurotransmission and apoptotic cell death by inhibiting the trophic effect mediated by the NMDA receptor whereas chronic ethanol treatment and withdrawal results in an enhanced toxic response toward glutamate. The neurobiology of human alcoholism such as ethanol intoxication, dependence, withdrawal seizures, delirium tremens, Wernicke-Korsakoff syndrome, and fetal alcohol syndrome can be better understood as a spectrum of consequences of ethanol's effect on the NMDA glutamatergic system.     

Watching neurotransmission in vitro

A new chip with a capability to read genomes uses arrays of tiny pH sensors on an integrated circuit to sequence DNA without the need for optics.     

A fight for neurotransmission: SCRAPPER trashes RIM

The presynaptic scaffold molecule RIM1alpha is important for regulating neurotransmitter release. In this issue, Yao et al. (2007) show in mice that an E3 ubiquitin ligase, SCRAPPER, targets a set of presynaptic proteins including RIM1alpha for degradation by the ubiquitin-proteasome system. Their results identify protein degradation as a mechanism for holding rapid synaptic communication in check.     

Somatostatin inhibits adrenergic and cholinergic neurotransmission in smooth muscle.

Somatostatin reduced the response to field stimulation in the guinea pig ileum and reduced the spontaneous contractions in the rabbit jejunum, an effect that was blocked by tetrodotoxin. Somatostatin also inhibited field stimulated alpha adrenergic contractions in the rat vas deferens and rabbit ear artery. However, the responses to direct application of either acetylcholine in the ileum or to norepinephrine in the ear artery or vas deferens were not affected by somatostatin. These results strongly suggest that somatostatin inhibits neuronal release of cholinergic and adrenergic transmitter substances in smooth muscle.     

Role of Astrocytes in Pain

Over the last decade, a series of studies has demonstrated that glia in the central nervous system play roles in many aspects of neuronal functioning including pain processing. Peripheral tissue damage or inflammation initiates signals that alter the function of the glial cells (microglia and astrocytes in particular), which in turn release factors that regulate nociceptive neuronal excitability. Like immune cells, these glial cells not only react at sites of central and/or peripheral nervous system damage but also exert their action at remote sites from the focus of injury or disease. As well as extensive evidence of microglial involvement in various pain states, there is also documentation that astrocytes are involved, sometimes seemingly playing a more dominant role than microglia. The interactions between astrocytes, microglia and neurons are now recognized as fundamental mechanisms underlying acute and chronic pain states. This review focuses on recent advances in understanding of the role of astrocytes in pain states.     

Primary Cultures of Astrocytes: Their Value in Understanding Astrocytes in Health and Disease

Neurochemical Research - During the past few decades of astrocyte research it has become increasingly clear that astrocytes have taken a central position in all central nervous system activities....     

Astrocytes in the epileptic brain

The roles that astrocytes play in the evolution of abnormal network excitability in chronic neurological disorders involving brain injury, such as acquired epilepsy, are receiving renewed attention due to improved understanding of the molecular events underpinning the physiological functions of astrocytes. In epileptic tissue, evidence is pointing to enhanced chemical signaling and disrupted linkage between water and potassium balance by reactive astrocytes, which together conspire to enhance local synchrony in hippocampal microcircuits. Reactive astrocytes in epileptic tissue both promote and oppose seizure development through a variety of specific mechanisms; the new findings suggest several novel astrocyte-related targets for drug development.     

Astrocytes and Epilepsy

Neurochemical Research - Changes in astrocyte channels, transporters, and metabolism play a critical role in seizure generation and epilepsy. In particular, alterations in astrocyte potassium,...     

The effect of cadmium on adrenergic neurotransmission in vitro.

The effect of cadmium on the response of isolated perfused rabbit ear arteries to nerve stimulation and norepinephrine administration was examined. Cadmium in concentrations of .075–.25μM caused enhancement of the pressor responses to nerve stimulation, but higher concentrations caused inhibition of the response. The pressor response to norepinephrine was also inhibited by cadmium, but required a 100x higher concentration than that needed for inhibition of the response to nerve stimulation. The dual effect of cadmium on the response to nerve stimulation suggests a plausible explanation for the conflicting reports in the literature regarding the blood pressure effects of cadmium exposure. The enhancement by low concentrations of cadmium of the response to nerve stimulation provides a possible mechanism for cadmium-induced hypertension.     

Roles of glutamine in neurotransmission

Glutamine (Gln) is found abundantly in the central nervous system (CNS) where it participates in a variety of metabolic pathways. Its major role in the brain is that of a precursor of the neurotransmitter amino acids: the excitatory amino acids, glutamate (Glu) and aspartate (Asp), and the inhibitory amino acid, γ-amino butyric acid (GABA). The precursor-product relationship between Gln and Glu/GABA in the brain relates to the intercellular compartmentalization of the Gln/Glu(GABA) cycle (GGC). Gln is synthesized from Glu and ammonia in astrocytes, in a reaction catalyzed by Gln synthetase (GS), which, in the CNS, is almost exclusively located in astrocytes (Martinez-Hernandez et al., 1977). Newly synthesized Gln is transferred to neurons and hydrolyzed by phosphate-activated glutaminase (PAG) to give rise to Glu, a portion of which may be decarboxylated to GABA or transaminated to Asp. There is a rich body of evidence which indicates that a significant proportion of the Glu, Asp and GABA derived from Gln feed the synaptic, neurotransmitter pools of the amino acids. Depolarization-induced-, calcium- and PAG activity-dependent releases of Gln-derived Glu, GABA and Asp have been observed in CNS preparations in vitro and in the brain in situ. Immunocytochemical studies in brain slices have documented Gln transfer from astrocytes to neurons as well as the location of Gln-derived Glu, GABA and Asp in the synaptic terminals. Patch-clamp studies in brain slices and astrocyte/neuron co-cultures have provided functional evidence that uninterrupted Gln synthesis in astrocytes and its transport to neurons, as mediated by specific carriers, promotes glutamatergic and GABA-ergic transmission. Gln entry into the neuronal compartment is facilitated by its abundance in the extracellular spaces relative to other amino acids. Gln also appears to affect neurotransmission directly by interacting with the NMDA class of Glu receptors. Transmission may also be modulated by alterations in cell membrane polarity related to the electrogenic nature of Gln transport or to uncoupled ion conductances in the neuronal or glial cell membranes elicited by Gln transporters. In addition, Gln appears to modulate the synthesis of the gaseous messenger, nitric oxide (NO), by controlling the supply to the cells of its precursor, arginine. Disturbances of Gln metabolism and/or transport contribute to changes in Glu-ergic or GABA-ergic transmission associated with different pathological conditions of the brain, which are best recognized in epilepsy, hepatic encephalopathy and manganese encephalopathy.