Synaptic Elements Research Articles

Structural organization, neurochemical characteristics, and connections of the reticular nucleus of the thalamus

This review analyzes current concepts of the structural organization and ultrastructure of the reticular nucleus of the thalamus (RNT) and the neurochemical characteristics of its neurons. The topography, cytoarchitectonics, and neuronal organization of this nucleus are considered in detail, as are questions of its neurogenesis. Neurochemical data clarifying the representation of neurotransmitter systems in the RNT and data on neuropeptides synthesized in its neurons are systematized. The complex ultrastructural organization of the RNT is characterized in terms of recent data from state-of-the-art immunocytochemical methods allowing localization of glutamatergic and GABAergic receptors on synaptic elements. Data on the afferent and efferent connections of the RNT demonstrate its influences on various parts of the brain and the specific features of its interactions with cortical formations.

C‐terminal synaptic targeting elements for postsynaptic density proteins ProSAP1/Shank2 and ProSAP2/Shank3

Synapses are specialized contact sites mediating communication between neurons. Synaptogenesis requires the specific assembly of protein clusters at both sides of the synaptic contact by mechanisms that are barely understood. We studied the synaptic targeting of multi-domain proteins of the ProSAP/Shank family thought to serve as master scaffolding molecules of the postsynaptic density. In contrast to Shank1, expression of green-fluorescent protein (GFP)-tagged ProSAP1/Shank2 and ProSAP2/Shank3 deletion constructs in hippocampal neurons revealed that their postsynaptic localization relies on the integrity of the C-termini. The shortest construct that was perfectly targeted to synaptic sites included the last 417 amino acids of ProSAP1/Shank2 and included the C-terminal sterile alpha motif (SAM) domain. Removal of 54 residues from the N-terminus of this construct resulted in a diffuse distribution in the cytoplasm. Altogether, our data delineate a hitherto unknown targeting signal in both ProSAP1/Shank2 and ProSAP2/Shank3 and provide evidence for an implication of these proteins and their close homologue, Shank1, in distinct molecular pathways.

Early changes in Huntington’s disease patient brains involve alterations in cytoskeletal and synaptic elements

Huntington's disease (HD) is caused by a polyglutamine repeat expansion in the N-terminus of the huntingtin protein. Huntingtin is normally present in the cytoplasm where it may interact with structural and synaptic elements. The mechanism of HD pathogenesis remains unknown but studies indicate a toxic gain-of-function possibly through aberrant protein interactions. To investigate whether early degenerative changes in HD involve alterations of cytoskeletal and vesicular components, we examined early cellular changes in the frontal cortex of HD presymptomatic (PS), early pathological grade (grade 1) and late-stage (grade 3 and 4) patients as compared to age-matched controls. Morphologic analysis using silver impregnation revealed a progressive decrease in neuronal fiber density and organization in pyramidal cell layers beginning in presymptomatic HD cases. Immunocytochemical analyses for the cytoskeletal markers alpha -tubulin, microtubule-associated protein 2, and phosphorylated neurofilament demonstrated a concomitant loss of staining in early grade cases. Immunoblotting for synaptic proteins revealed a reduction in complexin 2, which was marked in some grade 1 HD cases and significantly reduced in all late stage cases. Interestingly, we demonstrate that two synaptic proteins, dynamin and PACSIN 1, which were unchanged by immunoblotting, showed a striking loss by immunocytochemistry beginning in early stage HD tissue suggesting abnormal distribution of these proteins. We propose that mutant huntingtin affects proteins involved in synaptic function and cytoskeletal integrity before symptoms develop which may influence early disease onset and/or progression.

Glial modulation of synaptic transmission in culture

Accumulating evidence has demonstrated the existence of bidirectional communication between glial cells and neurons, indicating an important active role of glia in the physiology of the nervous system. Neurotransmitters released by presynaptic terminals during synaptic activity increase intracellular Ca(2+) concentration in adjacent glial cells. In turn, activated glia may release different transmitters that can feed back to neuronal synaptic elements, regulating the postsynaptic neuronal excitability and modulating neurotransmitter release from presynaptic terminals. As a consequence of this evidence, a new concept of the synaptic physiology, the tripartite synapse, has been proposed, in which glial cells play an active role as dynamic regulatory elements in neurotransmission. In the present article we review evidence showing the ability of astrocytes to modulate synaptic transmission directly, with the focus on studies performed on cell culture preparations, which have been proved extremely useful in the characterization of molecular and cellular processes involved in astrocyte-mediated neuromodulation.

Gaussian synapse ANNs in multi- and hyperspectral image data analysis

A new type of artificial neural network is used to identify different crops and ground elements from hyperspectral remote sensing data sets. These networks incorporate Gaussian synapses and are trained using a specific algorithm called Gaussian synapse back propagation described here. Gaussian synapses present an intrinsic filtering ability that permit concentrating on what is relevant in the spectra and automatically discard what is not. The networks are structurally adapted to the problem complexity as superfluous synapses and/or nodes are implicitly eliminated by the training procedure, thus pruning the network to the required size straight from the training set. The fundamental difference between the present proposal and other ANN topologies using Gaussian functions is that the latter use these functions as activation functions in the nodes, while in our case, they are used as synaptic elements, allowing them to be easily shaped during the training process to produce any type of n-dimensional discriminator. This paper proposes a multi- and hyperspectral image segmenter that results from the parallel and concurrent application of several of these networks providing a probability vector that is processed by a decision module. Depending on the criteria used for the decision module, different perspectives of the same image may be obtained. The resulting structure offers the possibility of resolving mixtures, that is, carrying out a spectral unmixing process in a very straightforward manner.

Interleukin-1 Mediates Pathological Effects of Microglia on Tau Phosphorylation and on Synaptophysin Synthesis in Cortical Neurons through a p38-MAPK Pathway

The presence of tangles of abnormally phosphorylated tau is a characteristic of Alzheimer's disease (AD), and the loss of synapses correlates with the degree of dementia. In addition, the overexpression of interleukin-1 (IL-1) has been implicated in tangle formation in AD. As a direct test of the requirement for IL-1 in tau phosphorylation and synaptophysin expression, IL-1 actions in neuron-microglia cocultures were manipulated. Activation of microglia with secreted beta-amyloid precursor protein or lipopolysaccharide elevated their expression of IL-1alpha, IL-1beta, and tumor necrosis factor alpha (TNFalpha) mRNA. When such activated microglia were placed in coculture with primary neocortical neurons, a significant increase in the phosphorylation of neuronal tau was accompanied by a decline in synaptophysin levels. Similar effects were evoked by treatment of neurons with recombinant IL-1beta. IL-1 receptor antagonist (IL-1ra) as well as anti-IL-1beta antibody attenuated the influence of activated microglia on neuronal tau and synaptophysin, but anti-TNFalpha antibody was ineffective. Some effects of microglial activation on neurons appear to be mediated by activation of p38 mitogen-activated protein kinase (p38-MAPK), because activated microglia stimulated p38-MAPK phosphorylation in neurons, and an inhibitor of p38-MAPK reversed the influence of IL-1beta on tau phosphorylation and synaptophysin levels. Our results, together with previous observations, suggest that activated microglia may contribute to neurofibrillary pathology in AD through their production of IL-1, activation of neuronal p38-MAPK, and resultant changes in neuronal cytoskeletal and synaptic elements.

DISC1-immunoreactive cells in the human brain

Theories concerning the pathology of human neurodevelopmental disorders that emerge in adolescence, such as schizophrenia, often hypothesize that there may be a failure of normal cortical synaptic loss or pruning. However, direct evidence that synaptic regression is a major developmental event in the adolescent human cortex is limited. Furthermore, developmental work in rodents suggested that synaptic regression in adolescence is not a major feature of cortical development. Thus, we set out to determine when and to what extent molecular markers of synaptic terminals [synaptophysin (SYP), SNAP-25, syntaxin1A (STX1A), and vesicle-associated membrane protein 1 (VAMP1)] are reduced during postnatal human life spanning from 1 month to 45 years (n = 69) using several different quantitative methods, microarray, qPCR and immunoblotting. We found little evidence for a consistent decrease in synaptic-related molecular markers at any time point, but instead found clear patterns of gradual increases in expression of some presynaptic markers with postnatal age (including SNAP-25, VAMP1 and complexin 1 (CPLX1) mRNAs and 6/6 presynaptic proteins evaluated). A measure of synaptic plasticity [growth-associated protein of 43 kDa (GAP-43)] was elevated in neonates, and continued robust expression throughout life. Since CPLX1 protein is enriched in inhibitory terminals we also tested if the protein product of complexin 2 (CPLX2), which is enriched in excitatory neurons, is more specifically reduced in development. In contrast to CPLX1, which showed a steady increase in both mRNA and protein levels during postnatal development (both r > 0.58, p < 0.001), CPLX2 mRNA decreased from infants to toddlers (r = −0.56, p < 0.001), while CPLX2 protein showed a steady increase until young adulthood (r = 0.55, p < 0.001). Furthermore, we found that indices of the dendrites [microtubule associated protein 2 (MAP2)] and spines (spinophilin and postsynaptic density protein of 95 kDa (PSD95)] showed some evidence of reduction over time at the mRNA level but the opposite pattern, of a developmental increase, was found for PSD95 and spinophilin protein levels. Taken together, the postnatal changes in molecular components of synapses supports the notion that growth and strengthening of synaptic elements is a major developmental event occurring in the frontal cortex throughout childhood and that maintenance of steady state levels of synapse-associated molecules may predominate during human adolescence.

Trajectories of brain development: point of vulnerability or window of opportunity?

Brain development is a remarkable process. Progenitor cells are born, differentiate, and migrate to their final locations. Axons and dendrites branch and form important synaptic connections that set the stage for encoding information potentially for the rest of life. In the mammalian brain, synapses and receptors within most regions are overproduced and eliminated by as much as 50% during two phases of life: immediately before birth and during the transitions from childhood, adolescence, to adulthood. This process results in different critical and sensitive periods of brain development. Since Hebb (1949) first postulated that the strengthening of synaptic elements occurs through functional validation, researchers have applied this approach to understanding the sculpting of the immature brain. In this manner, the brain becomes wired to match the needs of the environment. Extensions of this hypothesis posit that exposure to both positive and negative elements before adolescence can imprint on the final adult topography in a manner that differs from exposure to the same elements after adolescence. This review endeavors to provide an overview of key components of mammalian brain development while simultaneously providing a framework for how perturbations during these changes uniquely impinge on the final outcome.

Depression, III: treatments.

Back to table of contents Previous article Next article Images in NeuroscienceFull AccessDepression, III: TreatmentsHusseini Manji, Ph.D., Husseini ManjiSearch for more papers by this author, Ph.D., Bethesda, Md.Published Online:1 Jan 2003https://doi.org/10.1176/appi.ajp.160.1.24AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Antidepressant treatments are currently targeted to synaptic elements that regulate concentrations of serotonin and norepinephrine at the postsynaptic monoamine receptors. Drug development for mood disorders has relied heavily on this focus in the past; so heavily, in fact, that there is little mechanistic diversity among current antidepressant drugs. Recently, however, investigations into the mechanisms of antidepressant actions have focused on downstream intracellular elements that are modulated by chronic, but not acute, antidepressant administration, particularly the intracellular signaling pathways mediating cellular resilience and neuroplasticity. Two of these intracellular signaling pathways (involving the neuroprotective protein bcl-2 and brain-derived neurotrophic factor [BDNF]), altered by both antidepressants and mood stabilizers, are known to be neuroprotective and to mediate neurotrophic events. One pathway first involves signaling by growth factors (especially BDNF) through the intracellular enzymes ERK and RSK followed by CREB activation, leading ultimately to an increase in the transcription of bcl-2 (see Figure). A second pathway involves the activation of the G protein-related enzymes adenylate cyclase and protein kinase A, followed by CREB activation, leading subsequently to an increase in the expression of BDNF, one of the cellular growth factors. We already know that antidepressant treatment increases CREB phosphorylation (i.e., CREB activation) in the brain of rats. Antidepressants and ECT each increase the expression of BDNF. Chronic antidepressant treatment results in neurogenesis (i.e., new neuronal birth) in the hippocampus of rats (and presumably of humans). Lithium and valproate each increase the expression of bcl-2 at least in part through activation of the ERK-MAP intracellular cascade. Lithium is frankly neuroprotective in several animal models of neurodegeneration and actually increases gray matter volumes (possibly through reversal of illness-related atrophy) in patients with bipolar disorder. In addition, enhancement of neurotrophic pathways is apparent by both antidepressant and mood-stabilizing treatments. Thus, a potential novel target for treatment development in mood disorders will be medications with neurotrophic properties, some examples of which are under development currently, including phosphodiesterase (PDE4) inhibitors and AMPA receptor modulators (which increase BDNF expression).Address reprint requests to Dr. Tamminga, Maryland Psychiatric Research Center, University of Maryland, P.O. Box 21247, Baltimore, MD 21228; [email protected] (e-mail). Image courtesy of Dr. Manji. FiguresReferencesCited byDetailsCited By, Vol. 813Aplicación clínica de marcadores periféricos de respuesta a la terapia antidepresiva: neurotrofinas y citocinasRevista Colombiana de Psiquiatría, Vol. 41, No. 1Jornal Brasileiro de Psiquiatria, Vol. 55, No. 1American Journal of Health-System Pharmacy, Vol. 62, No. 23Pharmacotherapy, Vol. 24, No. 12 Volume 160Issue 1 January 2003Pages 24-24 Metrics PDF download History Published online 1 January 2003 Published in print 1 January 2003

A reliable primary human CNS culture protocol for morphological studies of dendritic and synaptic elements

Primary dissociated human fetal forebrain cultures were grown in defined serum-free conditions. At 4 weeks in vitro the cultures contained abundant morphologically well differentiated neurons with complex dendritic arbors. Astrocytic proliferation was negligible without the use of antimitotic agents. Confocal scanning laser microscopy (CSLM) and electron microscopy confirmed the presence of a dense neuropil, numerous cell–cell contacts and synapses. Neurons expressed a variety of proteins including growth associated protein-43 (GAP43), microtubule associated protein-2ab (MAP), class-III beta tubulin (C3BT), neurofilaments (NF), synaptophysin (SYN), parvalbumin (PA) and calbindin (CB). The cultures have proven to be reliable and simple to initiate and maintain for many weeks without passaging. They are useful in investigations of dendritic growth and injury of primary human CNS neurons.

Mechanisms underlying fictive feeding in aplysia: coupling between a large neuron with plateau potentials activity and a spiking neuron.

The buccal ganglia of Aplysia contain a central pattern generator (CPG) that organizes the rhythmic movements of the radula and buccal mass during feeding. Many of the cellular and synaptic elements of this CPG have been identified and characterized. However, the roles that specific cellular and synaptic properties play in generating patterns of activity are not well understood. To examine these issues, the present study developed computational models of a portion of this CPG and used simulations to investigate processes underlying the initiation of patterned activity. Simulations were done with the SNNAP software package. The simulated network contained two neurons, B31/B32 and B63. The development of the model was guided and constrained by the available current-clamp data that describe the properties of these two protraction-phase interneurons B31/B32 and B63, which are coupled via electrical and chemical synapses. Several configurations of the model were examined. In one configuration, a fast excitatory postsynaptic potential (EPSP) from B63 to B31/B32 was implemented in combination with an endogenous plateau-like potential in B31/B32. In a second configuration, the excitatory synaptic connection from B63 to B31/B32 produced both fast and slow EPSPs in B31/B32 and the plateau-like potential was removed from B31/B32. Simulations indicated that the former configuration (i.e., electrical and fast chemical coupling in combination with a plateau-like potential) gave rise to a circuit that was robust to changes in parameter values and stochastic fluctuations, that closely mimicked empirical observations, and that was extremely sensitive to inputs controlling the onset of a burst. The coupling between the two simulated neurons served to amplify exogenous depolarizations via a positive feedback loop and the subthreshold activation of the plateau-like potential. Once a burst was initiated, the circuit produced the program in an all-or-none fashion. The slow kinetics of the simulated plateau-like potential played important roles in both initiating and maintaining the burst activity. Thus the present study identified cellular and network properties that contribute to the ability of the simulated network to integrate information over an extended period before a decision is made to initiate a burst of activity and suggests that similar mechanisms may operate in the buccal ganglia in initiating feeding movements.

Synapse–Glia Interactions at the Mammalian Neuromuscular Junction

Perisynaptic Schwann cells (PSCs) play critical roles in regulating and stabilizing nerve terminals at the mammalian neuromuscular junction (NMJ). However, although these functions are likely regulated by the synaptic properties, the interactions of PSCs with the synaptic elements are not known. Therefore, our goal was to study the interactions between mammalian PSCs in situ and the presynaptic terminals using changes in intracellular Ca(2+) as an indicator of cell activity. Motor nerve stimulation induced an increase in intracellular Ca(2+) in PSCs, and this increase was greatly reduced when transmitter release was blocked. Furthermore, local application of acetylcholine induced Ca(2+) responses that were blocked by the muscarinic antagonist atropine and mimicked by the muscarinic agonist muscarine. The nicotinic antagonist alpha-bungarotoxin had no effect on Ca(2+) responses induced by acetylcholine. Local application of the cotransmitter ATP induced Ca(2+) responses that were unaffected by the P2 antagonist suramin, whereas local application of adenosine induced Ca(2+) responses that were greatly reduced by the A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT). However, the presence of the A1 antagonist in the perfusate did not block responses induced by ATP. Ca(2+) responses evoked by stimulation of the motor nerve were reduced in the presence of CPT, whereas atropine almost completely abolished them. Ca(2+) responses were further reduced when both antagonists were present simultaneously. Hence, PSCs at the mammalian NMJ respond to the release of neurotransmitter induced by stimulation of the motor nerve through the activation of muscarinic and adenosine A1 receptors.

Multiple microelectrode-recording system for human intracortical applications

The human brain is dominated by the neocortex, a large folded surface, whose cellular and synaptic elements are arranged in layers. Since cortical structure is relatively constant across its surface, local information processing can be inferred from multiple laminar recordings of its electrical activity along a line perpendicular to its surface. Such recordings need to be spaced at least as close together as the cortical layers, and need to be wideband in order to sample both low frequency synaptic currents as well as high-frequency action potentials. Finally, any device used in the human brain must comply with strict safety standards. The current paper presents details of a system meeting these criteria, together with sample results obtained from epileptic subjects undergoing acute or chronic intracranial monitoring for definition of the epileptogenic region.

The role of single neurons in information processing.

Neurons carry out the many operations that extract meaningful information from sensory receptor arrays at the organism's periphery and translate these into action, imagery and memory. Within today's dominant computational paradigm, these operations, involving synapses, membrane ionic channels and changes in membrane potential, are thought of as steps in an algorithm or as computations. The role of neurons in these computations has evolved conceptually from that of a simple integrator of synaptic inputs until a threshold is reached and an output pulse is initiated, to a much more sophisticated processor with mixed analog-digital logic and highly adaptive synaptic elements.

Glutamate-Induced White Matter Injury: Excitotoxicity without Synapses

White matter of the brain and spinal cord is irreversibly damaged by ischemia and trauma. Recent evidence indicates that despite the absence of synaptic elements, excitotoxic mechanisms play an important role in the pathogenesis of white matter damage. Glial cells, including astrocytes and oligodendrocytes, possess non-NMDA glutamate receptors and are injured by excessive exposure to AMPA/kainate agonists. In addition, the myelin sheath itself appears to respond directly to glutamate stimulation via AMPA receptors, which may also lead to injury of this key constituent of myelinated axons. During white matter anoxia/ischemia or trauma, endogenous glutamate is released mainly from axoplasmic pools in a nonvesicular fashion through Na+-dependent glutamate transporters, stimulated to operate in the glutamate efflux mode by collapse of transmembrane ion gradients and depolarization. It appears that parallel mechanisms are triggered by injurious stimuli, involving reverse Na+-Ca2+ exchange and voltage-gated Ca2+ channels producing Ca2+ overload of the axon cylinder, whereas glutamate release with AMPA receptor overactivation causes Ca2+-dependent damage to the ensheathing myelin and sup-porting glia. The emerging complexity of white matter injury mechanisms requires a thorough understanding of the interrelated steps to optimize therapeutic design.

Enhanced learning after genetic overexpression of a brain growth protein

Ramón y Cajal proposed 100 years ago that memory formation requires the growth of nerve cell processes. One-half century later, Hebb suggested that growth of presynaptic axons and postsynaptic dendrites consequent to coactivity in these synaptic elements was essential for such information storage. In the past 25 years, candidate growth genes have been implicated in learning processes, but it has not been demonstrated that they in fact enhance them. Here, we show that genetic overexpression of the growth-associated protein GAP-43, the axonal protein kinase C substrate, dramatically enhanced learning and long-term potentiation in transgenic mice. If the overexpressed GAP-43 was mutated by a Ser --> Ala substitution to preclude its phosphorylation by protein kinase C, then no learning enhancement was found. These findings provide evidence that a growth-related gene regulates learning and memory and suggest an unheralded target, the GAP-43 phosphorylation site, for enhancing cognitive ability.

Heat shock proteins Hsp27 and Hsp32 localize to synaptic sites in the rat cerebellum following hyperthermia

Stressful stimuli activate the heat shock (stress) response in which a set of heat shock proteins (hsps) is induced, which play roles in cellular repair and protective mechanisms. Most studies in the mammalian nervous system have focused on Hsp70, however, the present investigation targets other members of the induced set, namely Hsp27 and Hsp32. In response to hyperthermia, these hsps are strongly induced in Bergmann glial cells in the rat brain and transported into their radial fibers, which project into the `synaptic-enriched' molecular layer of the cerebellum. Using subcellular fractionation and immunoelectron microscopy, hyperthermia-induced Hsp27 and Hsp32 were detected in synaptic elements and in perisynaptic glial processes. These results suggest that stress-induced Hsp27 and Hsp32 may contribute to repair and protective mechanisms at the synapse.

A second promoter provides an alternative target for therapeutic up-regulation of utrophin in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an inherited muscle-wasting disease caused by the absence of a muscle cytoskeletal protein, dystrophin. We have previously shown that utrophin, the autosomal homologue of dystrophin, is able to compensate for the absence of dystrophin in a mouse model of DMD; we have therefore undertaken a detailed study of the transcriptional regulation of utrophin to identify means of effecting its up-regulation in DMD muscle. We have previously isolated a promoter element lying within the CpG island at the 5' end of the gene and have shown it to be synaptically regulated in vivo. In this paper, we show that there is an alternative promoter lying within the large second intron of the utrophin gene, 50 kb 3' to exon 2. The promoter is highly regulated and drives transcription of a widely expressed unique first exon that splices into a common full-length mRNA at exon 3. The two utrophin promoters are independently regulated, and we predict that they respond to discrete sets of cellular signals. These findings significantly contribute to understanding the molecular physiology of utrophin expression and are important because the promoter reported here provides an alternative target for transcriptional activation of utrophin in DMD muscle. This promoter does not contain synaptic regulatory elements and might, therefore, be a more suitable target for pharmacological manipulation than the previously described promoter.

Microglia in Alzheimer's Disease and Transgenic Models: How Close the Fit?

Research on microglia has grown nearly exponentially over the last two decades, 1 fueled in part by the recognition that inflammation plays a role in the pathogenesis of Alzheimer’s disease (AD). 2 Whereas their existence as a distinct central nervous system (CNS) cell type was once debated, it is now widely accepted that microglia are monocyte-derived cells that enter the CNS at early stages of development as highly mobile, ameboid cells that are distributed widely throughout the brain and spinal cord, developing a highly ramified phenotype that eventually forms a uniform reticular array in both gray and white matter. Being related to other cells of the mononuclear phagocytic system they are considered to be poised for activation, each cell policing a discrete and nonoverlapping domain and acting as a sentinel to disruption of the normal homeostasis of the neural tissue. 3 Microglia respond rapidly to subtle alterations not associated with any apparent tissue damage such as spreading electrical depression 4 as well as more severe insults such as anoxic-ischemic injury and neuronal loss associated with a host of degenerative disorders with a sequence of antigenic and morphological changes. The latter form is less ramified, with more abundant cytoplasm in soma and cell processes. It has cell markers, such as class II major histocompatibility antigen, that are barely detectable in the ramified form and is referred to as activated. The full repertoire of ramified microglia is not known, but they appear to be long-lived cells with a limited potential to divide, which contrasts with perivascular macrophages. 5 The latter have a more dynamic life cycle and enter and leave the CNS compartment more readily throughout the life of the individual. The perivascular macrophage, which constitutively express class II major histocompatibility antigen (HLA-DR) participates in the immune response and is fully capable of antigen presentation. 6 The phagocytic potential of the perivascular macrophage is not disputed, but whether ramified microglia are phagocytic cells is debated. Progressive transformation of ramified microglia to macrophages has been shown in a limited number of demyelinating conditions, where it appears that at least some microglia may differentiate into brain macrophages. 3,7

Use-dependent AMPA receptor block in mice lacking GluR2 suggests postsynaptic site for LTP expression.

The mechanisms responsible for enhanced transmission during long-term potentiation (LTP) at CA1 hippocampal synapses remain elusive. Several popular models for LTP expression propose an increase in 'use' of existing synaptic elements, such as increased probability of transmitter release or increased opening of postsynaptic receptors. To test these models directly, we studied a GluR2 knockout mouse in which AMPA receptor transmission is rendered sensitive to a use-dependent block by polyamine compounds. This method can detect increases during manipulations affecting transmitter release or AMPA receptor channel open time and probability, but shows no such changes during LTP. Our results indicate that the recruitment of new AMPA receptors and/or an increase in the conductance of these receptors is responsible for the expression of CA1 LTP.