Changes In Receptor Composition Research Articles

Astrocytes as a Source for Extracellular Matrix Molecules and Cytokines

Research of the past 25 years has shown that astrocytes do more than participating and building up the blood-brain barrier and detoxify the active synapse by reuptake of neurotransmitters and ions. Indeed, astrocytes express neurotransmitter receptors and, as a consequence, respond to stimuli. Within the tripartite synapse, the astrocytes owe more and more importance. Besides the functional aspects the differentiation of astrocytes has gained a more intensive focus. Deeper knowledge of the differentiation processes during development of the central nervous system might help explaining and even help treating neurological diseases like Alzheimer’s disease, Amyotrophic lateral sclerosis, Parkinsons disease, and psychiatric disorders in which astrocytes have been shown to play a role. Specific differentiation of neural stem cells toward the astroglial lineage is performed as a multi-step process. Astrocytes and oligodendrocytes develop from a multipotent stem cell that prior to this has produced primarily neuronal precursor cells. This switch toward the more astroglial differentiation is regulated by a change in receptor composition on the cell surface and responsiveness to Fibroblast growth factor and Epidermal growth factor (EGF). The glial precursor cell is driven into the astroglial direction by signaling molecules like Ciliary neurotrophic factor, Bone Morphogenetic Proteins, and EGF. However, the early astrocytes influence their environment not only by releasing and responding to diverse soluble factors but also express a wide range of extracellular matrix (ECM) molecules, in particular proteoglycans of the lectican family and tenascins. Lately these ECM molecules have been shown to participate in glial development. In this regard, especially the matrix protein Tenascin C (Tnc) proved to be an important regulator of astrocyte precursor cell proliferation and migration during spinal cord development. Nevertheless, ECM molecules expressed by reactive astrocytes are also known to act mostly in an inhibitory fashion under pathophysiological conditions. Thus, we further summarize resent data concerning the role of chondroitin sulfate proteoglycans and Tnc under pathological conditions.

Nicotine-induced monoamine neurotransmitter changes in the brain of young rats

A number of studies in various species including man indicated a greater risk of drug preference and addictive behavior in young as compared to adults. Such age dependent preference was also found with nicotine. To examine possible mechanisms for this difference in our continuing study of reward mechanisms, we compared nicotine-induced neurotransmitter changes in the brain regions of adult and young Sprague-Dawley rats, assaying the transmitters via microdialysis in conscious freely moving animals. In general, nicotine-induced changes were significantly less in the regions measured in the young. Nicotine-induced effects on dopamine in the dorsal and ventral hippocampus (VH), prefrontal and medial temporal cortex, and superior cerebral peduncle were lower in the young than in adult, the same in the ventral tegmental area (VTA) and lateral septal nucleus (LS), and somewhat higher in the nucleus accumbens shell (NAccS). Norepinephrine levels in the young were lower in all areas except in the VH where they were the same, and serotonin levels were lower except in the VTA and LS where they remained the same, and higher in the NAccS. Age-dependent differences in the metabolites measured were more mixed. We conclude that the greater nicotine preference in young is not paralleled by a greater effect of nicotine on the release of monoamines at least in most of the brain areas assayed. Thus, increases of nicotine reward are not likely due to increases of monoamines in reward and cognitive areas. The small increase of dopamine (DA) and more significant increase of serotonin (5-HT) only in the NAccS are of significance, and would indicate a more significant role of 5-HT than of DA at least in the age difference in nicotine preference. Developmental changes in receptor composition and distribution involving several transmitter systems and other components such as neuropeptides are also likely to play a role.

Expression of N-methyl- d-aspartate (NMDA) receptor subunits and splice variants in an animal model of long-term voluntary alcohol self-administration

Long-term, free-choice, alcohol self-administration with repeated alcohol deprivation phases is known to enhance N-methyl- d-aspartate (NMDA) receptor activity. We hypothesized that this might not only reflect an increase in NMDA receptor density, but that differential transcriptional regulation and alternative splicing of the various subunits comprising the NMDA receptor may lead to changes in receptor composition and subsequent function. We, therefore, aimed to further investigate this effect in various brain regions. The relative mRNA expression of exon 5 inclusion/exclusion variants of the NR1 subunit, and the relative expression of NR2A, NR2B and NR2C subunits was examined in rats subjected to long-term free-choice, alcohol self-administration with repeated alcohol deprivation phases. We observed a relative decrease of the NR2C/NR2A mRNA ratio and an increase of NR1 splice variants including exon 5 (NR1 + E5) in the striatum but not in the cortex, hippocampus or cerebellum in the experimental group. Our results demonstrate that long-term voluntary alcohol self-administration, affects the regulation of genes encoding the various subunits and splice variants of the NMDA receptor in a brain regional-specific manner.

Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABA A synaptic receptors

Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute phencyclidine (PCP), an antagonist of the N-methyl- D-aspartate (NMDA) receptor subtype. In this study we tested the hypothesis that chronic treatment of rats with this antagonist may be a more appropriate animal model than acute exposure since it could result in adaptive synaptic responses that would model certain aspects of the schizophrenic state in humans. In vitro intracellular electrophysiological recordings employing brain slices from rats treated chronically in vivo with PCP demonstrated that chronic PCP caused a substantial increase in synaptic responses mediated by NMDA receptors without any significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABA A receptor-mediated inhibitory responses were depressed significantly. Pharmacological and paired-pulse facilitation experiments demonstrated that these adaptive responses following chronic PCP administration were not the result of altered glutamate or GABA release. Immunoblot analyses suggest that the hyperfunctional NMDA response is at least partially mediated by an increased synthesis of NR1 and NR2A subunits as well as a change in the subunit stoichiometry of the NMDA receptor. This change in receptor composition was also supported by pharmacological experiments with a subunit selective NMDA antagonist. Our data support a reconsideration of NMDA and GABA A receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.

Receptor activation and homer differentially control the lateral mobility of metabotropic glutamate receptor 5 in the neuronal membrane.

Glutamate receptors are clustered at the membrane through interactions with intracellular scaffolding proteins and cytoskeletal elements but can also be found in intracellular compartments or dispersed in the membrane. This distribution results from an equilibrium between the different pools of receptors whose dynamic is poorly known. The group I metabotropic glutamate receptor 5 (mGluR5) is concentrated in an annulus around the postsynaptic density but also found in large amounts in the extrasynaptic membrane. To analyze the dynamic of stabilization of mGluR5, we used single-particle tracking, force measurements, and fluorescence recovery to measure the mobility of mGluR5. We found that receptor activation increases receptor diffusion, whereas the scaffolding protein Homer favors confinement of receptor movements within clusters of Homer-mGluR5. However, this stabilization is reversible, because even in the presence of Homer, receptors still enter and exit from clusters at fast rates. Furthermore, clusters themselves are highly dynamic both in their movements and in their composition, which can vary within tens of seconds. Thus, exchange of receptors between dispersed and clustered states is fast and regulated during physiological processes. These properties may explain certain fast changes in receptor composition observed at postsynaptic densities.

Receptor Activation and Homer Differentially Control the Lateral Mobility of Metabotropic Glutamate Receptor 5 in the Neuronal Membrane

Glutamate receptors are clustered at the membrane through interactions with intracellular scaffolding proteins and cytoskeletal elements but can also be found in intracellular compartments or dispersed in the membrane. This distribution results from an equilibrium between the different pools of receptors whose dynamic is poorly known. The group I metabotropic glutamate receptor 5 (mGluR5) is concentrated in an annulus around the postsynaptic density but also found in large amounts in the extrasynaptic membrane. To analyze the dynamic of stabilization of mGluR5, we used single-particle tracking, force measurements, and fluorescence recovery to measure the mobility of mGluR5. We found that receptor activation increases receptor diffusion, whereas the scaffolding protein Homer favors confinement of receptor movements within clusters of Homer-mGluR5. However, this stabilization is reversible, because even in the presence of Homer, receptors still enter and exit from clusters at fast rates. Furthermore, clusters themselves are highly dynamic both in their movements and in their composition, which can vary within tens of seconds. Thus, exchange of receptors between dispersed and clustered states is fast and regulated during physiological processes. These properties may explain certain fast changes in receptor composition observed at postsynaptic densities.

Electrophysiological analysis of NMDA receptor subunit changes in the aging mouse cortex

NMDA receptors play an important role in memory processes and plasticity in the brain. We have previously demonstrated a significant decrease in NMDARε2 subunit mRNA and protein with increasing age in the C57Bl/6 mouse frontal cortex. In the present study, two-electrode voltage clamp electrophysiology on Xenopus oocytes injected with total RNA harvested from the frontal cortex of young and old C57Bl mice was used to detect changes in receptor composition during aging. Ifenprodil concentration–response curves, magnesium current–voltage curves, and single channel conductances were determined for native receptors. In addition, ifenprodil and magnesium curves were generated for recombinant NMDA receptors of varying subunit ratios. Ifenprodil dose–response curves for all receptors were biphasic. The low affinity component of the curve increased slightly with age, while the high affinity population decreased, mimicking recombinant receptors with decreasing levels of ε2. A decrease in maximal current was also observed in aged animals with decreased levels of ε2, although single channel conductances were identical between young and old mice. In addition, an increase in sensitivity to magnesium was observed for receptors from older animals. Results are consistent with the interpretation that the ε2 subunit is reduced in older mouse frontal cortex. A change in NMDA receptor subunit composition could influence memory processes during aging.