Modulation of intrinsic circuits by serotonin 5-HT3 receptors in developing ferret visual cortex

Serotonergic projections are widespread in the developing neocortex, but their functions are obscure. The effects of 5-HT3 receptor agonists on cortical circuit response properties were studied in slices of ferret primary visual cortex using high-speed optical imaging of voltage-sensitive dye signals and whole-cell patch-clamp recording. Activation of the 5-HT3 receptor decreased the amplitude and lateral extent of excitation throughout postnatal development. This effect peaks after eye opening, which indicates a function for serotonergic modulation of circuit responses during the period of refinement of cortical connections. Whole-cell patch-clamp recordings from single neurons revealed that synaptic responses evoked by white matter stimulation were reduced by 5-HT3 receptor agonists, whereas the frequency of spontaneous GABAergic synaptic currents was enhanced dramatically. This indicates that the modulation of spontaneous synaptic activity by fast-acting serotonin receptors is reflected in an inhibition of the circuit response, in line with the notion of background synaptic activity altering the spatiotemporal integration properties of cortical cells by changing their membrane potential and their electrotonic structure. These mechanisms may regulate the response properties of intrinsic circuits in both the adult and developing neocortex.     

Synaptic input and output of parvalbumin-immunoreactive neurons in the neostriatum of the rat

Previous studies have demonstrated that the calcium-binding protein parvalbumin, is located within a population of GABAergic interneurons in the neostriatum of the rat. Anatomical studies have revealed that these cells receive asymmetrical synaptic input from terminals that are similar to identified cortical terminals and that they innervate neurons with the ultrastructural features of medium spiny cells. Furthermore, electrophysiological studies suggest that some GABAergic interneurons in the neostriatum receive direct excitatory input from the cortex and inhibit medium spiny cells following cortical stimulation. The main objectives of the present study were (i) to determine whether parvalbumin-immunoreactive neurons in the rat receive direct synaptic input from the cortex, (ii) to determine whether parvalbumin-immunopositive axon terminals innervate identified striatal projection neurons and (iii) to chemically characterize this anatomical circuit at the fine structural level. Rats received stereotaxic injections of biocytin in the frontal cortex or injections of neurobiotin in the substantia nigra. Following an appropriate survival time, the animals were perfused and the brains were sectioned and treated to reveal the transported tracers. Sections containing the neostriatum were treated for simultaneous localization of the transported tracer and parvalbumin immunoreactivity. Tracer deposits in the cortex gave rise to massive terminal and fibre labelling in the neostriatum. Parvalbumin-immunoreactive elements located within fields of anterogradely labelled terminals were examined in the electron microscope and corticostriatal terminals were found to form asymmetrical synaptic specializations with all parts of parvalbumin-immunoreactive neurons that were examined. Tracer deposits in the substantia nigra produced retrograde labelling of a subpopulation of striatonigral neurons. Areas of the neostriatum and nucleus accumbens containing retrogradely labelled neurons and parvalbumin-immunoreactive structures were selected for electron microscopy. Parvalbumin-immunopositive axon terminals formed symmetrical synaptic specializations with the perikarya of retrogradely labelled medium spiny projection neurons. Postembedding immunocytochemistry for GABA revealed that parvalbumin-immunoreactive boutons in synaptic contact with medium spiny neurons were GABA-positive. These data demonstrate directly a neural circuit whereby cortical information may be passed to medium spiny cells, via GABAergic interneurons, in the form of inhibition and provide an anatomical substrate for the feed-forward inhibition that has been detected in spiny neurons in electrophysiological experiments.     

Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria

Synaptic NMDA-type glutamate receptors are anchored to the second of three PDZ (PSD-95/Discs large/ZO-1) domains in the postsynaptic density (PSD) protein PSD-95. Here, we report that citron, a protein target for the activated form of the small GTP-binding protein Rho, preferentially binds the third PDZ domain of PSD-95. In GABAergic neurons from the hippocampus, citron forms a complex with PSD-95 and is concentrated at the postsynaptic side of glutamatergic synapses. Citron is expressed only at low levels in glutamatergic neurons in the hippocampus and is not detectable at synapses onto these neurons. In contrast to citron, p135 SynGAP, an abundant synaptic Ras GTPase-activating protein that can bind to all three PDZ domains of PSD-95, and Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) are concentrated postsynaptically at glutamatergic synapses on glutamatergic neurons. CaM kinase II is not expressed and p135 SynGAP is expressed in less than half of hippocampal GABAergic neurons. Segregation of citron into inhibitory neurons does not occur in other brain regions. For example, citron is expressed at high levels in most thalamic neurons, which are primarily glutamatergic and contain CaM kinase II. In several other brain regions, citron is present in a subset of neurons that can be either GABAergic or glutamatergic and can sometimes express CaM kinase II. Thus, in the hippocampus, signal transduction complexes associated with postsynaptic NMDA receptors are different in glutamatergic and GABAergic neurons and are specialized in a way that is specific to the hippocampus.     

Silent synapses in the developing rat visual cortex: evidence for postsynaptic expression of synaptic plasticity

In the developing visual cortex activity-dependent refinement of synaptic connectivity is thought to involve synaptic plasticity processes analogous to long-term potentiation (LTP). The recently described conversion of so-called silent synapses to functional ones might underlie some forms of LTP. Using whole-cell recording and minimal stimulation procedures in immature pyramidal neurons, we demonstrate here the existence of functionally silent synapses, i.e., glutamatergic synapses that show only NMDA receptor-mediated transmission, in the neonatal rat visual cortex. The incidence of silent synapses strongly decreased during early postnatal development. After pairing presynaptic stimulation with postsynaptic depolarization, silent synapses were converted to functional ones in an LTP-like manner, as indicated by the long-lasting induction of AMPA receptor-mediated synaptic transmission. This conversion was dependent on the activation of NMDA receptors during the pairing protocol. The selective activation of NMDA receptors at silent synapses could be explained presynaptically by assuming a lower glutamate concentration compared with functional ones. However, we found no differences in glutamate concentration-dependent properties of NMDA receptor-mediated PSCs, suggesting that synaptic glutamate concentration is similar in silent and functional synapses. Our results thus support a postsynaptic mechanism underlying silent synapses, i.e., that they do not contain functional AMPA receptors. Synaptic plasticity at silent synapses might be expressed postsynaptically by modification of nonfunctional AMPA receptors or rapid membrane insertion of AMPA receptors. This conversion of silent synapses to functional ones might play a major role in activity-dependent synaptic refinement during development of the visual cortex.     

Anatomical evidence for a mechanism of lateral inhibition in the rat thalamus

The aim of this study was to determine whether or not thalamic reticular nucleus (Rt) neurons form synaptic connections with the thalamocortical (TC) neurons from which they receive synaptic contacts. Therefore, we examined, in adult rats, the relationships between single TC and Rt neurons, which had been marked simultaneously with an anterograde/retrograde tracer (biocytin or Neurobiotin), using the extracellular or juxtacellular technique. (i) From 30 successful extracellular microapplications of marker into the Rt, 22 gave retrogradely marked TC somatodendritic arbors at the fringe of or clear outside the anterogradely darkly stained Rt axon terminal fields. Following biocytin application into the thalamus, few cells were retrogradely stained in the Rt at the periphery of the anterogradely labelled axon terminal field. (ii) The juxtacellular filling of a single Rt cell was accompanied by the back-filling of a single TC neuron (n = 4 pairs), which presumably formed synaptic contacts with the former cell. The somatodendritic complex of the back-filled TC neuron was located outside the Rt cell's axonal arbor. These anatomical data provide clear evidence that Rt and thalamic neurons predominantly form between themselves open rather than closed loop connections. Because TC neurons make glutamatergic synapses onto Rt cells, which are GABAergic, and are the first elements synaptically activated by prethalamic afferents into the TC-Rt network, the present results strongly support the hypothesis that Rt neurons principally generate a mechanism of lateral inhibition in the thalamus.     

Synaptic effects of identified interneurons innervating both interneurons and pyramidal cells in the rat hippocampus

GABAergic interneurons sculpt the activity of principal cells and are themselves governed by GABAergic inputs. To determine directly some of the sources and mechanisms of this GABAergic innervation, we have used dual intracellular recordings with biocytin-filled microelectrodes and investigated synaptic interactions between pairs of interneurons in area CA1 of the adult rat hippocampus. Of four synaptically-coupled interneuron-to-interneuron cell pairs, three presynaptic cells were identified as basket cells, preferentially innervating somata and proximal dendrites of pyramidal cells, but one differing from the other two in the laminar distribution of its dendritic and axonal fields. The fourth presynaptic interneuron was located at the border between strata lacunosum moleculare and radiatum, with axon ramifying within stratum radiatum. Action potentials evoked in all four presynaptic interneurons were found to elicit fast hyperpolarizing inhibitory postsynaptic potentials (mean amplitude 0.35 +/- 0.10 mV at a membrane potential of -59 +/- 2.8 mV) in other simultaneously recorded interneurons (n=4). In addition, three of the presynaptic interneurons were also shown to produce similar postsynaptic responses in subsequently recorded pyramidal cells (n=4). Electron microscopic evaluation revealed one of the presynaptic basket cells to form 12 synaptic junctions with the perisomatic domain (seven somatic synapses and five synapses onto proximal dendritic shafts) of the postsynaptic interneuron in addition to innervating the same compartments of randomly-selected local pyramidal cells (50% somatic and 50% proximal dendritic synapses, n=12). In addition, light microscopic analysis also indicated autaptic self-innervation in basket (12 of 12) and bistratified cells (six of six). Electron microscopic investigation of one basket cell confirmed six autaptic junctions made by five of its boutons. Together, these data demonstrate that several distinct types of interneuron have divergent output to both principal cells and local interneurons of the same (basket cells) or different type. The fast synaptic effects, probably mediated by GABA in both postsynaptic interneurons and principal cells are similar. These additional sources of GABA identified here in the input to GABAergic cells could contribute to the differential temporal patterning of distinct GABAergic synaptic networks.     

Production of cytokines and metalloproteinases in rheumatoid synovitis is T cell dependent

Agrin, a proteoglycan secreted by motoneurons, is a critical organizer of synaptic differentiation at skeletal neuromuscular junctions. Agrin is widely expressed in the nervous system so other functions seem likely, but none have been demonstrated. To test roles for agrin in interneuronal synapse formation, we studied hippocampi from mutant mice that completely lack the z+ splice form of agrin essential for neuromuscular differentiation and also exhibit severely ( approximately 90%) reduced levels of all agrin isoforms (M. Gautam et al., 1996, Cell 85, 525-535). The brains of neonatal homozygous agrin mutants were often smaller than those of heterozygous and wild-type littermates, but were morphologically and histologically indistinguishable. In particular, antibodies to pre- and postsynaptic components of glutamatergic synapses were similarly coaggregated at synaptic sites in both mutants and controls. Because mutants die at birth due to neuromuscular defects, we cultured neurons to assess later stages of synaptic maturation. In primary cultures, the agrin-deficient neurons formed MAP2-positive dendrites and tau-1-positive axons. Synaptic vesicle proteins, AMPA- and NMDA-type glutamate receptors, GABAA receptors, and the putative synapse-organizing proteins PSD-95, GKAP, and gephyrin formed numerous clusters at synaptic sites. Quantitatively, the number of SV2-labeled contacts per neuron at day 5 and the number of PSD-95 clusters per dendrite length at day 18 in culture showed no significant differences between genotypes. Furthermore, exogenous z+ agrin was unable to induce ectopic accumulation of components of central glutamatergic or GABAergic synapses as it does for neuromuscular cholinergic synapses. These results indicate that the z+ forms of agrin are dispensable for glutamatergic and GABAergic synaptic differentiation in the central nervous system.     

In vivo activity-dependent plasticity at cortico-striatal connections: evidence for physiological long-term potentiation

The purpose of the present study was to investigate in vivo the activity-dependent plasticity of glutamatergic cortico-striatal synapses. Electrical stimuli were applied in the facial motor cortex and intracellular recordings were performed in the ipsilateral striatal projection field of this cortical area. Recorded cells exhibited the typical intrinsic membrane properties of striatal output neurons and were identified morphologically as medium spiny type I neurons. Subthreshold cortical tetanization produced either short-term posttetanic potentiation or short-term depression of cortically-evoked excitatory postsynaptic potentials. When coupled with a postsynaptic depolarization leading the membrane potential to a suprathreshold level, the tetanus induced long-term potentiation (LTP) of cortico-striatal synaptic transmission. Induction of striatal LTP was prevented by intracellular injection of a calcium chelator suggesting that this synaptic plasticity involves an increase of postsynaptic free calcium concentration. Contrasting with previous in vitro studies our findings demonstrate that LTP constitutes the normal form of use-dependent plasticity at cortico-striatal synapses. Since excitation of striatal neurons produces a disinhibition of premotor networks, LTP at excitatory striatal inputs should favor the initiation of movements and therefore could be critical for the functions of basal ganglia in motor learning.     

Some cholinergic themes related to Alzheimer's disease: synaptology of the nucleus basalis, location of m2 receptors, interactions with amyloid metabolism, and perturbations of cortical plasticity

Cholinergic neurons in the nucleus basalis of Meynert (nbM) receive cholinergic, GABAergic and monoaminergic synapses. Only few of these neurons display the sort of intense m2 immunoreactivity that would be expected if they were expressing m2 as their presynaptic autoreceptor. The depletion of cortical m2 in Alzheimer's disease (AD) appears to reflect the loss of presynaptic autoreceptors located on incoming axons from the nucleus basalis of Meynert (nbM) and also the loss of postsynaptic receptors located on a novel group of nitric oxide producing interstitial neurons in the cerebral cortex. The defect of cholinergic transmission in AD may enhance the neurotoxicity of amyloid beta, leading to a vicious cycle which can potentially accelerate the pathological process. Because acetylcholine plays a critical role in regulating axonal growth and synaptic remodeling, the cholinergic loss in AD can perturb cortical plasticity so as to undermine the already fragile compensatory reserve of the aging cerebral cortex.     

Pigeon basal ganglia: insights into the neuroanatomy underlying telencephalic sensorimotor processes in birds

This paper reviews the organization of the avian and mammalian striatum. The striatum receives input from virtually the entire rostrocaudal and mediolateral expanse of the cerebral cortex. The corticostriatal projections appear to be glutamatergic, forming excitatory synapses in the striatum. Another major projection to the avian striatum that also appears to be glutamatergic stems from a set of nuclei in the dorsal zone of the avian thalamus that are comparable to the mammalian intralaminar, mediodorsal, and midline nuclei. Furthermore, the striatum receives a massive projection from dopaminergic neurons of the ventral tegmental area and substantia nigra in the midbrain tegmentum. In return, the midbrain tegmentum receives a direct GABAergic/substance P-ergic/ dynorphinergic projection from the striatum, as well as an indirect one formed by GABAergic/substance P-ergic/ dynorphinergic and GABA-ergic/enkephalinergic striatal neurons projecting to the pallidum in the first step, and pallidal GABAergic/LANT6/parvalbumin neurons projecting to the midbrain tegmentum in the second step. In addition to its projection neurons, the striatum possesses GABAergic and cholinergic interneurons. One motor output pathway of the striatum runs via the pallidum and dorsal thalamic ventral tier nulei to the motor cortex. In addition to this pathway, birds possess a major descending pathway from the basal ganglia to the tectum via the GABAergic nucleus spiriformis lateralis in the pretectum. On hodological and topological grounds, similar nuclei, although not GABAergic, can be found in mammals. Finally, an other striatal motor output is formed by a sequential GABAergic pathway from the basal ganglia via the substantia nigra to the tectum. In conclusion, it appears that the organization of the avian and mammalian basal ganglia is similar rather than different.     

GABAA, NMDA and AMPA receptors: a developmentally regulated 'ménage à trois'

The main ionotropic receptors (GABAA, NMDA and AMPA) display a sequential participation in neuronal excitation in the neonatal hippocampus. GABA, the principal inhibitory transmitter in the adult CNS, acts as an excitatory transmitter in early postnatal stage. Glutamatergic synaptic transmission is first purely NMDA-receptor based and lacks functional AMPA receptors. Therefore, initially glutamatergic synapses are 'silent' at resting membrane potential, NMDA channels being blocked by Mg2+. However, when GABA and glutamatergic synapses are coactivated during the physiological patterns of activity, GABAA receptors can facilitate the activation of NMDA receptors, playing the role conferred to AMPA receptors later on in development. Determining the mechanisms underlying the development of this 'ménage à trois' will shed light not only on the wide range of trophic roles of glutamate and GABA in the developing brain, but also on the significance of the transition from neonatal to adult forms of plasticity.     

Fast synaptic signaling by nicotinic acetylcholine and serotonin 5-HT3 receptors in developing visual cortex

Cholinergic and serotonergic fiber systems invade the developing visual cortex several weeks before eye opening; both transmitters have been implicated in plasticity of neocortical circuits. These transmitters have been presumed to act predominantly through second messenger-coupled receptors, because fast cholinergic or serotonergic neurotransmission has never been observed in neocortex. However, acetylcholine and serotonin also act on ligand-gated ion channels; the nicotinic acetylcholine receptor and the serotonin 5-HT3 receptor, respectively. Here, using whole-cell patch-clamp techniques in developing ferret visual cortex, we pharmacologically isolated fast, spontaneous, and evoked cholinergic and serotonergic synaptic events in pyramidal cells and interneurons of all cortical layers. The number of cells receiving such inputs increased with the ingrowth of thalamic afferents, and the frequencies of the spontaneous events increased at eye opening. Thus, both acetylcholine and serotonin can mediate fast synaptic transmission in the visual cortex; the early onset of these mechanisms suggests a role during initial stages of circuit formation and during subsequent experience-dependent remodeling of cortical connections.     

Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type

In cultures of dissociated rat hippocampal neurons, persistent potentiation and depression of glutamatergic synapses were induced by correlated spiking of presynaptic and postsynaptic neurons. The relative timing between the presynaptic and postsynaptic spiking determined the direction and the extent of synaptic changes. Repetitive postsynaptic spiking within a time window of 20 msec after presynaptic activation resulted in long-term potentiation (LTP), whereas postsynaptic spiking within a window of 20 msec before the repetitive presynaptic activation led to long-term depression (LTD). Significant LTP occurred only at synapses with relatively low initial strength, whereas the extent of LTD did not show obvious dependence on the initial synaptic strength. Both LTP and LTD depended on the activation of NMDA receptors and were absent in cases in which the postsynaptic neurons were GABAergic in nature. Blockade of L-type calcium channels with nimodipine abolished the induction of LTD and reduced the extent of LTP. These results underscore the importance of precise spike timing, synaptic strength, and postsynaptic cell type in the activity-induced modification of central synapses and suggest that Hebb's rule may need to incorporate a quantitative consideration of spike timing that reflects the narrow and asymmetric window for the induction of synaptic modification.     

Characterization of cytokine and iNOS mRNA expression in situ during the course of experimental autoimmune myocarditis in rats

The distribution of GABAergic elements and their synaptic contacts in the nucleus submedius, a specific nociceptive relay in the medial thalamus of the cat, was studied using light and electron-microscopic postembedding immunohistochemical methods. About one-fourth of the neurons in nucleus submedius were GABA immunoreactive. These neurons were generally smaller than the unlabeled neurons and are probably local circuit neurons. Electron microscopy showed GABA immunoreactivity in two types of vesicle-containing profiles, F-terminals and presynaptic dendrites. F-terminals formed simple synapses with the dendrites of presumed thalamocortical relay cells. Presynaptic dendrites were involved in more complex synaptic arrangements that included ascending trigeminothalamic and spinothalamic tract terminals and thalamocortical relay cell dendrites. Analysis of single sections showed that about 40% of the trigeminothalamic and spinothalamic tract terminals, identified by anterograde transport of horseradish peroxidase, were presynaptic to GABAergic presynaptic dendrites. These results show that GABAergic neurons are frequent in nucleus submedius and that the GABAergic elements make synaptic connections similar to those described for other sensory relay nuclei, including the somatosensory ventroposterior nucleus. This suggests that GABAergic mechanisms play an important role in the processing of nociceptive and thermoreceptive information.     

The mammalian brain high-affinity L-proline transporter is enriched preferentially in synaptic vesicles in a subpopulation of excitatory nerve terminals in rat forebrain

The expression of a brain-specific high-affinity Na+-dependent (and Cl--dependent) L-proline transporter (PROT) in subpopulations of putative glutamatergic neurons in mammalian brain suggests a physiological role for this carrier in excitatory neurotransmission (). To gain insights into potential sites where PROT may function, we used a C-terminal domain antipeptide antibody to determine the regional distribution and subcellular localization of PROT in rat forebrain. PROT immunoreactivity was seen in processes having a regional light microscopic distribution comparable to that of known glutamatergic projections within the cortex, caudate putamen nucleus (CPN), hippocampal formation, and other forebrain regions. In all regions examined by electron microscopy (cortex, CPN, and the stratum oriens of CA1), PROT labeling was observed primarily within subpopulations of axon terminals forming asymmetric excitatory-type synapses. Immunogold labeling for PROT was detected in close contact with membranes of small synaptic vesicles (SSVs) and more rarely with the plasma membrane in these axon terminals. Subcellular fractionation studies confirmed the preferential distribution of PROT to synaptic vesicles. The topology of PROT in synaptic vesicles was found to be inverted with respect to the plasma membrane, suggesting that PROT-containing vesicles are generated by a process involving endocytosis from the plasma membrane. Because PROT lacks any of the known characteristics of other vesicular transporters, these results suggest that certain excitatory terminals have a reserve pool of PROT associated with SSVs. The delivery of PROT to the plasma membrane by exocytosis could play a critical role in the plasticity of certain glutamatergic pathways.     

The protein MAP-1B links GABA(C) receptors to the cytoskeleton at retinal synapses

The ionotropic type-A and type-C receptors for the neurotransmitter gamma-aminobutyric acid (GABA(A) and GABA(C) receptors) are the principal sites of fast synaptic inhibition in the central nervous system, but it is not known how these receptors are localized at GABA-dependent synapses. GABA(C) receptors, which are composed of rho-subunits, are expressed almost exclusively in the retina of adult vertebrates, where they are enriched on bipolar cell axon terminals. Here we show that the microtubule-associated protein 1B (MAP-1B) specifically interacts with the GABA(C) rho1 subunit but not with GABA(A) receptor subunits. Furthermore, GABA(C) receptors and MAP-1B co-localize at postsynaptic sites on bipolar cell axon terminals. Co-expression of MAP-1B and the rho1 subunit in COS cells results in a dramatic redistribution of the rho1 subunit. Our observations suggest a novel mechanism for localizing ionotropic GABA receptors to synaptic sites. This mechanism, which is specific for GABA(C) but not GABA(A) receptors, may allow these receptor subtypes, which have distinct physiological and pharmacological properties, to be differentially localized at inhibitory synapses.     

Effective peer responses to impaired nursing practice

Subplate neurons, the first neurons of the cerebral cortex to differentiate and mature, are thought to be essential for the formation of connections between thalamus and cortex, such as the system of ocular dominance columns within layer 4 of visual cortex. To learn more about the requirement for subplate neurons in the formation of thalamocortical connections, we have sought to identify the neurotransmitters and peptides expressed by the specific class of subplate neurons that sends axonal projections into the overlying visual cortex. To label retrogradely subplate neurons, fluorescent latex microspheres were injected into primary visual cortex of postnatal day 28 ferrets, just prior to the onset of ocular dominance column formation. Subsequently, neurons were immunostained with antibodies against glutamate, glutamic acid decarboxylase (GAD-67), parvalbumin, neuropeptide Y (NPY), somatostatin (SRIF), or nitric oxide synthase (NOS). Retrograde labeling results indicate that the majority of subplate neurons projecting into the cortical plate reside in the upper half of the subplate. Combined immunostaining and microsphere labeling reveal that about half of cortically projecting subplate neurons are glutamatergic; most microsphere-labeled subplate neurons do not stain for GAD-67, parvalbumin, NPY, SRIF, or NOS. These observations suggest that subplate neurons can provide a significant glutamatergic synaptic input to the cortical plate, including the neurons of layer 4. If so, excitation from the axons of subplate neurons may be required in addition to that from lateral geniculate nucleus neurons for the activity-dependent synaptic interactions that lead to the formation of ocular dominance columns during development.     

Connectivity and convergence of single corticostriatal axons

The distribution of synapses formed by corticostriatal neurons was measured to determine the average connectivity and degree of convergence of these neurons and to search for spatial inhomogeneities. Two kinds of axonal fields, focal and extended, and two striatal tissue compartments, the patch (striosome) and matrix, were analyzed separately. Electron microscopic examination revealed that both kinds of corticostriatal axons made synapses at varicosities that could be identified in the light microscope, and each varicosity made a single synapse. Thus, the distribution of varicosities was a good estimate of the spatial distribution of synapses. The distance between axonal varicosities was measured to determine the density of synaptic connections formed by one axon within the volume occupied by a striatal neuron. Intersynaptic distances were distributed exponentially, except that synapses were rarely located <4 microm apart. The mean distance between synapses was approximately 10 microm, so axons made a maximum of 40 synapses within the dendritic volume of a spiny neuron. There are approximately 2840 spiny neurons located within the volume of the dendrites of one spiny cell (Oorschot, 1996), so each axon must contact 相似文献   

Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala

Fear conditioning is a paradigm that has been used as a model for emotional learning in animals. The cellular correlate of fear conditioning is thought to be associative N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity within the amygdala. Here we show that glutamatergic synaptic transmission to inhibitory interneurons in the basolateral amygdala is mediated solely by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast to AMPA receptors at inputs to pyramidal neurons, these receptors have an inwardly rectifying current-voltage relationship, indicative of a high permeability to calcium. Tetanic stimulation of inputs to interneurons caused an immediate and sustained increase in the efficacy of these synapses. This potentiation required a rise in postsynaptic calcium, but was independent of NMDA receptor activation. The potentiation of excitatory inputs to interneurons was reflected as an increase in the amplitude of the GABA(A)-mediated inhibitory synaptic current in pyramidal neurons. These results demonstrate that excitatory synapses onto interneurons within a fear conditioning circuit show NMDA-receptor independent long-term potentiation. This plasticity might underlie the increased synchronization of activity between neurons in the basolateral amygdala after fear conditioning.     

A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia

In the primate cerebral cortex, morphologically and functionally diverse classes of local circuit neurons containing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) differentially regulate the activity of pyramidal cells, the principal type of excitatory output neurons. In schizophrenia, GABA neurotransmission in the prefrontal cortex (PFC) appears to be disturbed but whether specific populations of GABA neurons are affected is not known. The chandelier class of GABA neurons are of particular interest because their axon terminals, which form distinctive arrays termed "cartridges," provide inhibitory input exclusively to the axon initial segment of pyramidal cells. Thus, chandelier cells are positioned to powerfully regulate the excitatory output of pyramidal neurons and, consequently, to substantially affect the patterns of neuronal activity within the PFC. In this study, an antibody directed against the GABA membrane transporter GAT-1 was used to label GABA axon terminals in postmortem human brains. The relative density of GAT-1-immunoreactive axon cartridges furnished by chandelier neurons was decreased by 40% in the PFC of schizophrenic subjects compared with matched groups of normal control and nonschizophrenic psychiatric subjects. In contrast, markers of the axon terminals of other populations of GABA neurons were not altered in the schizophrenic subjects. Furthermore, the density of GAT-1-immunoreactive axon cartridges was not altered in psychiatric subjects who had been treated with antipsychotic medications. The changes in GAT-1-immunoreactive axon cartridges of chandelier neurons in schizophrenia are likely to reflect altered information processing within the PFC and in its output connections to other brain regions and could contribute to the cognitive impairments seen in this disorder.