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PubMed2005

NMDA receptor-dependent regulation of axonal and dendritic branching.

In the rodent trigeminal principal nucleus (PrV), trigeminal afferent terminals and postsynaptic cells form discrete modules ("barrelettes") that replicate the patterned array of whiskers and sinus hairs on the snout. Barrelette neurons of the PrV relay whisker-specific patterns to the contralateral thalamus and, subsequently, to the primary somatosensory barrel cortex. Genetic impairment of NMDA receptor (NMDAR) function blocks development of barrelettes in the PrV. Underlying cellular and functional defects are not known. Here, we examined morphological differentiation of whisker afferents, dendritic differentiation of barrelette cells, and their electrophysiological properties in mice with genetic perturbations of the essential subunit NR1 of NMDARs. We show that in NR1 gene knock-down (KD) and knock-out mice, whisker afferents begin their embryonic development normally but, over time, fail to segregate into patches, and instead they develop exuberant terminal arbors spanning most of the PrV. Postnatal NR1KD barrelette cells, with significantly reduced NMDA currents, retain their membrane and synaptic properties but develop longer dendrites with no orientation preference. These results indicate that NMDARs regulate growth of presynaptic terminal arbors and postsynaptic dendritic branching, thereby leading to consolidation of synapses and patterning of presynaptic and postsynaptic elements.

Animals↗
PubMed2003

Primary afferent terminals that express presynaptic NR1 in rats are mainly from myelinated, mechanosensitive fibers.

Presynaptic N-methyl-D-aspartate (NMDA) receptors in terminals of primary afferents to spinal cord of rats were first reported by Liu et al. (1994; Proc. Natl. Acad. Sci. USA 91:8383-8387) and were proposed to modulate nociceptive input (Liu et al. [1997] Nature 386:721-724). We previously demonstrated kainate and AMPA receptors in numerous primary afferent terminals in the spinal cord fixed with diluted paraformaldehyde and no glutaraldehyde. Therefore, we reinvestigated the occurrence of presynaptic NMDAR1 (NR1) with this fixation protocol. With confocal microscopy, numerous immunofluorescent puncta were double-stained for NR1 and the presynaptic marker synaptophysin throughout the spinal gray. NR1-immunostained puncta costained more frequently with a tracer that labels myelinated afferents (cholera toxin subunit B; CTB) than with a tracer that labels non-peptidergic unmyelinated afferents (Griffonia simplicifolia isolectin B4; IB4). Virtually no double staining was found for NR1 and calcitonin gene-related peptide (CGRP), which labels somatic peptidergic primary afferents. In the gracile nucleus, virtually all puncta labeled for CTB appeared immunopositive for NR1. At the electron microscopic level, most immunopositive terminals in spinal cord and gracile nucleus displayed morphological characteristics of endings of myelinated primary afferents. NR1 was presynaptic in 60-65% of all synapses in which it was expressed pre- or postsynaptically, or both, in spinal laminae I-IV. Estimates for the gracile nucleus were higher (80%). No presynaptic NR1 was found in the ventroposterior thalamus. Because of the relative sparsity of presynaptic NR1 in terminals in laminae I and IIo and in terminals of peptidergic unmyelinated afferents, it is suggested that presynaptic NMDA receptors play a more significant role in modulation of mechanosensitive, innocuous input than in nociception.

Animals↗
PubMed1998

Decreased striatal monoaminergic terminals in severe chronic alcoholism demonstrated with (+)[11C]dihydrotetrabenazine and positron emission tomography.

We used (+)[11C]dihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter, with positron emission tomography to study striatal monoaminergic presynaptic terminals in 7 male severe chronic alcoholic subjects without Wernicke-Korsakoff disease compared with 7 male normal controls of similar ages. We found reduced specific binding in the caudate nucleus and putamen in the alcoholic group, and the difference reached significance in the putamen. Specific binding was not decreased in the thalamus, which was examined as a reference structure. We also detected deficits in blood-to-brain transfer rate, K1, in the same regions of the alcoholic group, with a significant difference in the putamen. K1 was unchanged in the thalamus. The finding of reduced striatal VMAT2 in severe chronic alcoholic patients suggests that nigrostriatal monoaminergic terminals are reduced, with or without loss of neurons from the substantia nigra. The findings suggest that the damaging effects of severe chronic alcoholism on the central nervous system are more extensive than previously considered.

Adult↗
PubMed1994

Cerebellar-responsive neurons in the thalamic ventroanterior-ventrolateral complex of rats: light and electron microscopy.

The morphology and synaptic organization of neurons in the ventroanterior-ventrolateral nucleus of rats was examined using in vivo intracellular staining techniques. Neurons were characterized electrophysiologically based on intrinsic membrane properties and synaptic responses to stimulation of motor cortex and cerebellar nuclei, as described in the companion paper. Cerebellar-responsive neurons were stained intracellularly with either horseradish peroxidase or biocytin. All stained ventroanterior-ventrolateral nucleus neurons were identified as thalamocortical neurons on anatomical (and often electrophysiological) grounds, consistent with previous findings that rat ventroanterior-ventrolateral nucleus is interneuron-sparse. Ventroanterior-ventrolateral nucleus neurons had three to eight thick primary dendrites. Proximal dendrites often exhibited a tufted branching pattern, from which many thinner, higher order dendrites arose. Dendrites branched to form a funnel-like infiltration of the neuropil that resulted in a spherical, roughly homogeneous dendritic field. The axon originated from the cell body or a proximal dendrite and coursed laterally and dorsally to innervate motor cortex. One to five axon collaterals were emitted in the rostral dorsolateral sector of the thalamic reticular nucleus; collaterals were not observed in the ventroanterior-ventrolateral nucleus or other nuclei in dorsal thalamus. The synaptic organization of the ventroanterior-ventrolateral nucleus was examined with electron microscopy, including two intracellularly labeled ventroanterior-ventrolateral nucleus neurons that were shown electrophysiologically to receive monosynaptic inputs from the cerebellum. The neuropil of rat ventroanterior-ventrolateral nucleus lacked the complexity and diversity found in corresponding thalamic nuclei of felines and primates, due to the paucity of interneurons. Vesicle-containing dendrites, dendrodendritic synapses and glomeruli were not observed. Three broad classes of presynaptic terminals were identified. (1) Small round boutons: small boutons containing densely-packed, small round vesicles that formed asymmetric synapses predominantly with the distal dendrites of thalamocortical neurons. These were the most prevalent type of bouton in the ventroanterior-ventrolateral nucleus (78% of presynaptic elements) and likely arose from the cerebral cortex. (2) Large round boutons: large terminals with loosely packed small round vesicles that made multiple asymmetric synapses with proximal and intermediate dendrites. Large round boutons comprised 8% of the neuropil, and likely arose from the cerebellar nuclei. (3) Medium size boutons with pleomorphic vesicles: medium-sized profiles containing pleomorphic vesicles that formed symmetric synapses with proximal, intermediate and distal dendrites and, less frequently, with cell bodies.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Dynorphin exerts both postsynaptic and presynaptic effects in the Globus pallidus of the rat.

The opioids contained in striato-pallidal axons are thought to play a significant role in motor control. We examined post- and presynaptic effects of the kappa (kappa)-receptor agonist dynorphin A (1-13) (DYN13) on the globus pallidus (GP) neurons in rat brain slice preparations using the whole cell recording method. DYN13 hyperpolarized and decreased the input resistance of approximately one-quarter of neurons examined. All of these DYN13-sensitive neurons had medium-sized somata, large aspiny dendrites and generated repetitive firing without strong accommodation. The hyperpolarization was blocked by barium and was independent of TTX and intracellular chloride levels. The hyperpolarization was also selectively blocked by the kappa-antagonist nor-binaltorphimine dihydrochloride but not by the mu- or delta-antagonists. These data suggested that DYN13 activates barium-sensitive potassium currents in some GP neurons. Low- and high-intensity stimulation of the neostriatum (Str) evoked long- and short-latency GABAergic responses, respectively. Previous data suggested that the long- and the short-latency responses were due to activation of the striato-pallidal axons and the local collaterals of pallido-striatal axons, respectively. DYN13 diminished the amplitude of both the short- and long-latency GABAergic responses in all the neurons tested. The effects of DYN13 on GABAergic postsynaptic responses were also selectively blocked by a kappa-antagonist. To investigate whether the effects were pre- or postsynaptic, the effects of DYN13 on spontaneous inhibitory postsynaptic potentials (IPSPs) and TTX-independent miniature-inhibitory postsynaptic currents (IPSCs) were examined. DYN13 decreased the frequency, but not the amplitude, of spontaneous IPSCs and calcium-dependent miniature-IPSCs. However, DYN13 did not alter the cadmium-insensitive miniature-IPSCs. These results suggested that DYN13 suppressed GABA release from presynaptic terminals. This possibility was tested using a paired-stimulation test. DYN13 reduced the probability of evoking IPSCs to the first stimulation and greatly increased the success probability to the second stimulus. The amplitude of successfully evoked IPSCs was not changed with DYN13. DYN13 did not affect the excitatory postsynaptic potentials (EPSPs) or the response to iontophoretically applied GABA and glutamate. Together, these results suggest that DYN released from striato-pallidal axons controls the activity of GP neurons 1) by directly hyperpolarizing a population of neurons and 2) by presynaptically inhibiting GABA release from striato-pallidal and intrapallidal terminals.

Animals↗
PubMed1990

Potassium channel blockade differentially affects the relative refractory period of frog afferent terminals and axons.

1. The effects of potassium channel blockade on afferent axons and terminal regions in frog dorsal roots and spinal cords, respectively, were investigated in vitro. 2. A condition-test (C-T) protocol was used to assess the population relative refractory period. Characteristics of main axons were evaluated by stimulation at the proximal end of transected dorsal roots (DR). Characteristics of terminal regions were tested by stimulation at the base of the dorsal horn (DH). 3. DH recovery of excitability was delayed by low concentrations of 4-aminopyridine (4-AP) and tetraethylammonium (TEA) alone or combined. The same treatments did not affect recovery to DR stimulation. 4. DH recovery of excitability was not delayed by solutions suppressing terminal calcium influx. 5. We conclude that sensitivity of the relative refractory period to potassium channel blocking agents differs between main axons and axon terminal regions. This may indicate differences between axon terminals and main axons in the mechanism of action potential repolarization. 6. We hypothesize that rapid action potential repolarization by pharmacologically sensitive potassium channels in presynaptic terminal regions keeps terminal action potentials short. Terminal action potential brevity would limit calcium influx, thus preventing terminal calcium overload but contributing to transmission failures at spinal synapses.

4-Aminopyridine↗
PubMed1993

High-resolution imaging of protein phosphorylation in squid axons and synapse by electron energy loss spectroscopy.

We demonstrate that clusters of phosphorus atoms can be detected in energy loss spectroscopic images (ESI) of cytoskeletal proteins of squid axons. In series of images taken at four energy windows below and three windows above the phosphorus P-L2,3 ionization edge, signal-to-background intensity differences were analyzed by videodensitometry. A distinct increase of relative intensities was recorded above the phosphorus edge in neurofilaments of the peripheral giant axon and in those of the presynaptic terminal. A high level of neurofilament phosphorylation in the peripheral axon supports previous biochemical and immunochemical results, but our finding of phosphorylated neurofilaments in the presynaptic axon conflicts with these studies. Our method may be advantageous for analysis with high elemental and spatial resolution of the phosphorylation state of cytoskeletal protein molecules in situ.

Animals↗
PubMed1996

Piccolo, a novel 420 kDa protein associated with the presynaptic cytomatrix.

In this study, we describe a novel 420 kDa protein, called Piccolo, found at a wide variety of adult rat brain synapses. High protein levels in the cerebellum, the olfactory bulb and the hippocampus were frequently observed to be associated with asymmetric type 1 synapses. Piccolo is selectively enriched in presynaptic terminals, but is not a component of synaptic vesicles (SVs). Immunogold electron microscopy revealed that Piccolo localizes to the amorphous material among SVs at the presynaptic plasma membrane. Biochemical studies showed that it is very tightly bound to this structure. Thus, we speculate that Piccolo is a structural component of the presynaptic cytomatrix which anchors SVs to the presynaptic plasmalemma.

Animals↗
PubMed1989

Membrane depolarization evokes neurotransmitter release in the absence of calcium entry.

The discovery that Ca2+ is necessary for the release of neurotransmitter, the primary means by which nerve cells communicate, led to the calcium hypothesis of neutransmitter release, in which release is initiated after an action potential only by an increase in intracellular Ca2+ concentration near the release sites and is terminated (1-2 ms) by the rapid removal of Ca2+. Since then, the calcium-voltage hypothesis has been proposed, in which the depolarization of the presynaptic terminals has two functions. First, in common with the calcium hypothesis, the Ca2+ conductance is increased, thereby permitting Ca2+ entry. Second, a conformational change is induced in a membrane molecule that renders it sensitive to Ca2+, and then binding of Ca2+ to this active form triggers release of neurotransmitter. When the membrane is repolarized, the molecule is inactivated and release is terminated, regardless of the local Ca2+ concentration at that moment. This hypothesis, in contrast to the calcium hypothesis, accounts for the insensitivity of the time course of release to experimental manipulations of intracellular Ca2+ concentration. Furthermore, it explains rapid termination of release after depolarization, even though Ca2+ concentration may still be high. Here we describe experiments that distinguish between these two hypotheses and find that our results support the calcium voltage hypothesis.

Action Potentials↗
PubMed1991

Presynaptic facilitation at the crayfish neuromuscular junction. Role of calcium-activated potassium conductance.

Membrane potential was recorded intracellularly near presynaptic terminals of the excitor axon of the crayfish opener neuromuscular junction (NMJ), while transmitter release was recorded postsynaptically. This study focused on the effects of a presynaptic calcium-activated potassium conductance, gK(Ca), on the transmitter release evoked by single and paired depolarizing current pulses. Blocking gK(Ca) by adding tetraethylammonium ion (TEA; 5-20 mM) to a solution containing tetrodotoxin and aminopyridines caused the relation between presynaptic potential and transmitter release to steepen and shift to less depolarized potentials. When two depolarizing current pulses were applied at 20-ms intervals with gK(Ca) not blocked, the presynaptic voltage change to the second (test) pulse was inversely related to the amplitude of the first (conditioning) pulse. This effect of the conditioning prepulse on the response to the test pulse was eliminated by 20 mM TEA and by solutions containing 0 mM Ca2+/1 mM EGTA, suggesting that the reduction in the amplitude of the test pulse was due to activation of gK(Ca) by calcium remaining from the conditioning pulse. In the absence of TEA, facilitation of transmitter release evoked by a test pulse increased as the conditioning pulse grew from -40 to -20 mV, but then decreased with further increase in the conditioning depolarization. A similar nonmonotonic relationship between facilitation and the amplitude of the conditioning depolarization was reported in previous studies using extracellular recording, and interpreted as supporting an additional voltage-dependent step in the activation of transmitter release. We suggest that this result was due instead to activation of a gK(Ca) by the conditioning depolarization, since facilitation of transmitter release increased monotonically with the amplitude of the conditioning depolarization, and the early time course of the decay of facilitation was prolonged when gK(Ca) was blocked. The different time courses for decay of the presynaptic potential (20 ms) and facilitation (greater than 50 ms) suggest either that residual free calcium does not account for facilitation at the crayfish NMJ or that the transmitter release mechanism has a markedly higher affinity or stoichiometry for internal free calcium than does gK(Ca). Finally, our data suggest that the calcium channels responsible for transmitter release at the crayfish NMJ are not of the L, N, or T type.

Action Potentials↗
PubMed1999

Presynaptic effects of muscarine on ACh release at the frog neuromuscular junction.

1. Presynaptic effects of muscarine on neurotransmitter release were studied at the frog neuromuscular junction, using focal depolarization of the presynaptic terminal to different levels. 2. Muscarine (10 microM) had a dual effect on ACh release: concomitant inhibition and enhancement of release at the same patch of presynaptic membrane. 3. These two effects were maximal at low depolarizing pulses and diminished as depolarization increased. 4. At low depolarizing pulses, atropine (1 microM) enhanced release, suggesting that ACh in the synaptic cleft causes a net tonic inhibition of ACh release. 5. In the presence of the M2 antagonist methoctramine (1 microM), muscarine (10 microM) enhanced ACh release. 6. In the presence of the M1 antagonist pirenzepine (10 microM), muscarine (10 microM) produced stronger inhibition. 7. These results show that the M2 receptor is responsible for inhibition of ACh release, while the M1 receptor is responsible for its enhancement. 8. The inhibitory effect of muscarine did not depend on extracellular [Ca2+]. Enhancement of release was abolished at low extracellular [Ca2+]. 9. The muscarine inhibitory effect was not associated with a reduction of Ca2+ current, while release enhancement was associated with an increase of Ca2+ current.

Acetylcholine↗
PubMed1999

"Apoptotic" biochemical cascades in synaptic compartments: roles in adaptive plasticity and neurodegenerative disorders.

Apoptosis is a form of cell death historically defined by morphological and biochemical changes that occur in the cell body and nucleus. However, in contrast to nonneuronal cells in which apoptosis has been most intensively studied, neurons exhibit elaborate morphologies with synaptic connections often located at sites a great distance from the cell body. Signaling events occurring in synaptic terminals are believed to play important roles in either promoting (e.g., activation of glutamate receptors in postsynaptic spines) or preventing (e.g., activation of neurotrophic factors in presynaptic terminals) neuronal cell death in various physiological and pathological settings. We have found that apoptotic biochemical cascades can be activated locally in synaptic terminals and neurites and have shown that such cascades can result in local functional and morphological alterations and can also propagate to the cell body resulting in neuronal death. Prostate apoptosis response-4 production, caspase activation, loss of plasma membrane phospholipid asymmetry, mitochondrial dysfunction, and production of factors capable of inducing nuclear chromatin condensation and fragmentation can all occur locally in synaptic terminals in response to various stimuli. Activation of receptors for neurotrophic factors (e.g., basic fibroblast growth factor, secreted form of amyloid precursor protein alpha, and activity-dependent neurotrophic factor) and cytokines (e.g., tumor necrosis factor-alpha) in synaptic terminals can exert synaptoprotective actions that either can be transduced locally or may require signals to the nucleus and back. In addition to their roles in synaptic degeneration and neuron death, apoptotic cascades may play roles in synaptic plasticity. For example, we found that caspase activation can lead to proteolysis of certain glutamate receptor subunits and that this action of capases is correlated with reduced calcium responses to glutamate. We propose that apoptotic cascades function in a continuum in which low levels of activation play roles in adaptive responses to "stressors," whereas higher levels of activation mediate synaptic degeneration and cell death.

Animals↗
PubMed1994

Cysteine strings, calcium channels and synaptic transmission.

Multidisciplinary studies have led to the discovery and characterization of cysteine string proteins (csps) in both Drosophila and Torpedo. Phenotypic analysis of csp mutants in Drosophila demonstrates a crucial role for csp in synaptic transmission. Expression studies of Torpedo csp (Tcsp) in Xenopus oocytes suggests that the protein has some role in the function of presynaptic Ca2+ channels. However, biochemical purification of Tcsp indicates that is associated with synaptic vesicles rather than with the plasma membrane of presynaptic terminals where Ca2+ channels reside. These results suggest a model in which csps serve as a link by which docked synaptic vesicles could modulate the activity of presynaptic Ca2+ channels.

Animals↗
PubMed1985

Ultrastructural characterization of gonadotropin-releasing hormone (GnRH)-producing neurons.

By means of preembedding immunohistochemistry, two types of gonadotropin-releasing hormone (GnRH) positive neurons in the rat could be identified and characterized in the preoptic region and in the diagonal band: (1) a "smooth" GnRH neuron with relatively even cytoplasmic contours, and (2) a "spiny" GnRH neuron with thorn-like protrusions of the perikaryon and cell processes. Both cell types contain the same organelles in similar number and distribution, but they differ in the number of synaptic contacts. In general, GnRH cell bodies have a large round or ovoid nucleus, well-developed rough endoplasmic reticulum arranged in multilayered stacks or as individual cisternae, and several Golgi complexes. Lysosomes are not numerous under the conditions studied. Specializations include kinocilia, nematosomes, and lamellar whorls. Throughout the cytoplasm, scattered dense core vesicles with a diameter of 100 nm and clear vesicles with a diameter of 30-40 nm can be seen with a preferential localization close to the cell membrane. The cell processes of smooth GnRH cells close to the perikaryal appear as extensions of the perikaryal cytoplasm with all organelles except the nucleus. The two neurites originate from the perikaryon as tapering cones over a distance of 200-300 micron, until they reach a diameter of 0.5-3 micron. Cell processes of spiny GnRH cells show bifurcations, protrusions, or invaginations and contain clear and dense core vesicles in their spines. In areas distant from the perikaryon, immunoreactive fibers with a large number of dense core and clear vesicles can occasionally be seen to terminate synaptically or asynaptically on other neurons. The GnRH neurons show postsynaptic specializations at the level of the perikaryon and at cell processes, when apposed by a presynaptic terminal. Such synaptic contacts are seen less frequently on smooth cells than on spiny cells. Large areas of the GnRH cell may be covered by a thin glial lamella, which separates the cell body from the surrounding neuropil. The results indicate the existence of two populations of GnRH cell bodies with different patterns of innervation, which suggest different integrative capacities.

Animals↗
PubMed1991

gamma-Aminobutyric acid and mu-opioid receptor localization and adaptation in the basal forebrain.

In conclusion, GABAA receptors containing the alpha 1 subunit are localized on postsynaptic neurons in the ventral pallidum, mainly in the dorsolateral compartment and on presynaptic terminals in the nucleus accumbens. mu-opioid receptors are localized on postsynaptic neurons in both the nucleus accumbens and ventral pallidum, and therefore may be regulating presynaptic release of enkephalin from the accumbens-pallidal projection. Discrete lesions in the dorsomedial core of the nucleus accumbens will upregulate GABAA receptors in the dorsolateral compartment of the nucleus accumbens in a fashion similar to the upregulation of GABAA receptors in the globus pallidus after striatal lesions. However, larger lesions of the lateral core projection to the dorsolateral compartment of the ventral pallidum do not upregulate the GABAA receptors, suggesting that the mechanisms for upregulation of GABAA receptors are specific to the dorsomedial core or a smaller lesion. The uniqueness of the compartments within the nucleus accumbens and the ventral pallidum are supported by these receptor and mRNA analyses.

Acclimatization↗
PubMed1984

4-Aminopyridine-induced ultrastructural alterations of pinched-off nerve terminals from rat cerebral cortex.

Pinched-off nerve terminals (synaptosomes) from rat cerebral cortex were depolarized with 60 mM KCl and treated with 20 mM 4-aminopyridine in order to evaluate ultrastructural alterations. The empty presynaptic terminals were counted and their number was given as a percentage of the normal terminals. The proportion of empty terminals increased from 10.47 +/- 1.56% to 32.45 +/- 1.88% (P less than 0.001) following treatment with 20 mM 4-aminopyridine. This effect of 4-aminopyridine depended on the presence of Ca++ in the incubation medium. The results are discussed in terms of facilitation by 4-aminopyridine of exocytotic transmitter release. We think that the increase of the empty synaptosomes was due to the exhaustion or inhibition of the synaptic vesicle recycling mechanism.

4-Aminopyridine↗
PubMed2003

Angiotensin type 1 receptor immunoreactivity in the thoracic spinal cord.

The angiotensin II type 1 receptor (AT1R) in the central nervous system (CNS) plays a pivotal role in determining blood pressure. However, the relationship of the receptor to neurones in the spinal cord which are the final CNS contribution to sympathetic outflow is unknown. Here we first use RT-PCR to show that AT1A, AT1B and AT2 receptors are expressed in thoracic spinal cord of the rat. Using light microscopic immunohistochemistry we find that the AT1 receptor in the thoracic spinal cord is located on neurones and ependymal cells. Neurones with extensive immunostaining of somata and dendrites were located in the intermediolateral cell column (IML) and lamina X (the central autonomic area), regions associated with autonomic outflow, as well as in lamina V. Retrograde labelling and dual immunolabelling with nNOS revealed that those AT1R-immunopositive cells in the IML were sympathetic preganglionic neurones, while those in lamina X were unlikely to be. Punctate labelling resembling that of axonal fibres and terminals was evident in lamina II of the dorsal horn and throughout the cord. Electron microscopy in the IML and lamina X revealed that these puncta were presynaptic terminals, but also astrocyte processes. Immunolabelling was also evident beneath the plasma membrane in neuronal somata. These data show that the AT1R in the spinal cord is ideally located to influence autonomic outflow and hence participate in the CNS determination of blood pressure.

Animals↗
PubMed1997

Dystrophin in the retina.

Dystrophin is a plasma membrane-associated cytoskeletal protein of the spectrin superfamily. The dystrophin cytoskeleton has been first characterized in muscle. Muscular 427 kDa dystrophin binds to subplasmalemmal actin filaments via its amino-terminal domain. The carboxy-terminus of dystrophin binds to a plasma membrane anchor, beta-dystroglycan, which is associated on the external side with the extracellular matrix receptor, alpha-dystroglycan, that binds to the basal lamina proteins laminin-1, laminin-2, and agrin. In the muscle, the dystroglycan complex is associated with the sarcoglycan complex that consists of several glycosylated, integral membrane proteins. The absence or functional deficiency of the dystrophin cytoskeleton is the cause of several types of muscular dystrophies including the lethal Duchenne muscular dystrophy (DMD), one of the most severe and most common genetic disorders of man. The dystrophin complex is believed to stabilize the plasma membrane during cycles of contraction and relaxation. Muscular dystrophin and several types of dystrophin variants are also present in extramuscular tissues, e.g. in distinct regions of the central nervous systems including the retina. Absence of dystrophin from these sites is believed to be responsible for some extramuscular symptoms of DMD, e.g. mental retardation and disturbances in retinal electrophysiology (reduced b-wave in electroretinograms). The reduced b-wave in electroretinograms indicated a disturbance of neurotransmission between photoreceptors and ON-bipolar cells. At least two different dystrophin variants are present in photoreceptor synaptic complexes. One of these dystrophins (Dp260) is virtually exclusively expressed in the retina. In the neuroretina, dystrophin is found in significant amounts in the invaginated photoreceptor synaptic complexes. At this location dystrophin colocalizes with dystroglycan. Agrin, an extracellular ligand of alpha-dystroglycan, is also present at this location whereas the proteins of the sarcoglycan complex appear to be absent in photoreceptor synaptic complexes. Dystrophin and dystroglycan are located distal from the ribbon-containing active synaptic zones where both proteins are restricted to the photoreceptor plasma membrane bordering on the lateral sides of the synaptic invagination. In addition, some neuronal profiles of the postsynaptic complex also contain dystrophin and beta-dystroglycan. These profiles appear to belong at least in part to projections of the photoreceptor terminals into the postsynaptic dendritic complex. In view of the abnormal neurotransmission between photoreceptors and ON-bipolar cells in DMD patients the dystrophin/beta-dystroglycan-containing projections of photoreceptor presynaptic terminals into the postsynaptic dendritic plexus might somehow modify the ON-bipolar pathway. Another retinal site associated with dystrophin/beta-dystropglycan is the plasma membrane of Müller cells where dystrophin/beta-dystroglycan appear to be present at particular high concentrations. At this location the dystrophin/dystroglycan complex may play a role in the attachment of the retina to the vitreous, and, under pathological conditions, in traction-induced retinal detachment.

Animals↗