Direct Visualization and Mapping of the Spatial Course of Fiber Tracts at Microscopic Resolution in the Human Hippocampus.

While hippocampal connectivity is essential to normal memory function, our knowledge of human hippocampal circuitry is largely inferred from animal studies. Using polarized light microscopy at 1.3 µm resolution, we have directly visualized the 3D course of key medial temporal pathways in 3 ex vivo human hemispheres and 2 ex vivo vervet monkey hemispheres. The multiple components of the perforant path system were clearly identified: Superficial sheets of fibers emanating from the entorhinal cortex project to the presubiculum and parasubiculum, intermixed transverse and longitudinal angular bundle fibers perforate the subiculum and then project to the cornu ammonis (CA) fields and dentate molecular layer, and a significant alvear component runs from the angular bundle to the CA fields. From the hilus, mossy fibers localize to regions of high kainate receptor density, and the endfolial pathway, mostly investigated in humans, merges with the Schaffer collaterals. This work defines human hippocampal pathways underlying mnemonic function at an unprecedented resolution.

Mnemonic discrimination relates to perforant path integrity: An ultra-high resolution diffusion tensor imaging study.

Pattern separation describes the orthogonalization of similar inputs into unique, non-overlapping representations. This computational process is thought to serve memory by reducing interference and to be mediated by the dentate gyrus of the hippocampus. Using ultra-high in-plane resolution diffusion tensor imaging (hrDTI) in older adults, we previously demonstrated that integrity of the perforant path, which provides input to the dentate gyrus from entorhinal cortex, was associated with mnemonic discrimination, a behavioral outcome designed to load on pattern separation. The current hrDTI study assessed the specificity of this perforant path integrity-mnemonic discrimination relationship relative to other cognitive constructs (identified using a factor analysis) and white matter tracts (hippocampal cingulum, fornix, corpus callosum) in 112 healthy adults (20-87 years). Results revealed age-related declines in integrity of the perforant path and other medial temporal lobe (MTL) tracts (hippocampal cingulum, fornix). Controlling for global effects of brain aging, perforant path integrity related only to the factor that captured mnemonic discrimination performance. Comparable integrity-mnemonic discrimination relationships were also observed for the hippocampal cingulum and fornix. Thus, whereas perforant path integrity specifically relates to mnemonic discrimination, mnemonic discrimination may be mediated by a broader MTL network.

Anatomical observations including morphometric pattern of foramina transversaria of atlas vertebrae in North Indians

The Foramen Transversarium (FT) is the result of a special formation of cervical transverse processes formed by fusion of vestigial costal elements to the body and true transverse process of the atlas that transmits the vertebral vascular bundle. The aim of this study was to investigate the morphology and variations, if any, in the FT of the atlas which can compromise the course of the vertebral artery leading to its insufficiency. Sixty foramina transversaria of 30 dry adult human atlas vertebrae obtained from the Anatomy Department, Government Medical College, Amritsar, Punjab, India, were employed to carry out this study. Linear measurements of FT Length, Width and Depth were carried out with the help of a vernier caliper. On the basis of shape, 5 different types of FT, i.e. Rounded, Elliptical-Anteroposterior, Elliptical Transverse, Elliptical Right-Left and Elliptical Left Right, were classified. The presence of unilateral and bilateral accessory foramina transversaria was also noted. Results indicate that the mean of right and left sides of FT Length was 6.81 mm, Width 5.28 mm and Depth 5.39 mm respectively. The most common shape of the FT was Type 4 with highest frequency of 56.6% (17) on the right side and 33.3% (10) on the left side. Out of 30 vertebrae, only 7(23.3%) presented accessory FT, 4 (13.3%) showed single FT, 1 (3.3%) showed double FT unilaterally on the left side and 2 vertebrae (6.6%) presented single accessory FT bilaterally. To conclude, morphological and morphometric knowledge of the FT is clinically important as the Vertebral Artery passing through it contributes blood supply not only to the brain, but also to the inner ear, and its compression may lead to neurological and labyrinthine disturbances. FT variations are also helpful in the interpretation of radiographic pictures or CT scans for diagnostics

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An analysis of entorhinal cortex projections to the dentate gyrus, hippocampus, and subiculum of the neonatal macaque monkey.

The entorhinal cortex is the primary interface between the hippocampal formation and neocortical sources of sensory information. Although much is known about the cells of origin, termination patterns, and topography of the entorhinal projections to other fields of the adult hippocampal formation, very little is known about the development of these pathways, particularly in the human or nonhuman primate. We have carried out experiments in which the anterograde tracers (3) H-amino acids, biotinylated dextran amine, and Phaseolus vulgaris leucoagglutinin were injected into the entorhinal cortex in 2-week-old rhesus monkeys (Macaca mulatta). We found that the three fiber bundles originating from the entorhinal cortex (the perforant path, the alvear pathway, and the commissural connection) are all established by 2 weeks of age. Fundamental features of the laminar and topographic distribution of these pathways are also similar to those in adults. There is evidence, however, that some of these projections may be more extensive in the neonate than in the mature brain. The homotopic commissural projections from the entorhinal cortex, for example, originate from a larger region within the entorhinal cortex and terminate much more densely in layer I of the contralateral entorhinal cortex than in the adult. These findings indicate that the overall topographical organization of the main cortical afferent pathways to the dentate gyrus and hippocampus are established by birth. These findings add to the growing body of literature on the development of the primate hippocampal formation and will facilitate further investigations on the development of episodic memory.

Cognitive processing speed in older adults: relationship with white matter integrity.

Cognitive processing slows with age. We sought to determine the importance of white matter integrity, assessed by diffusion tensor imaging (DTI), at influencing cognitive processing speed among normal older adults, assessed using a novel battery of computerized, non-verbal, choice reaction time tasks. We studied 131 cognitively normal adults aged 55-87 using a cross-sectional design. Each participant underwent our test battery, as well as MRI with DTI. We carried out cross-subject comparisons using tract-based spatial statistics. As expected, reaction time slowed significantly with age. In diffuse areas of frontal and parietal white matter, especially the anterior corpus callosum, fractional anisotropy values correlated negatively with reaction time. The genu and body of the corpus callosum, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus were among the areas most involved. This relationship was not explained by gray or white matter atrophy or by white matter lesion volume. In a statistical mediation analysis, loss of white matter integrity mediated the relationship between age and cognitive processing speed.

A new approach to location of the dentate gyrus and perforant path in rats/mice by landmarks on the skull.

The hippocampus has important roles in learning and memory. Many in vivo experiments require accurate location of a certain region of the hippocampus, long-term potentiation (LTP) recording being one of them. In vitro and in vivo studies can be used to measure LTP in the hippocampus. It is more difficult in vivo to locate the specific brain region than in vitro. Location of the dentate gyrus (DG) and perforant path (PP) is usually achieved using brain stereotaxic atlasses. Because the data in the atlasses were obtained from a particular rat/mouse strain (Rat: adult Wistar, 290 g; Mouse: adult C57BL/J6, 26-30 g), the data in atlases could not be easily applied in all the different other strains of these species. We describe a method that uses landmarks on the skull to locate these structures in both species, which has been successfully applied in BALB/c mice, KM mice, SAMP8, SAMR1 and Wistar rats; making it a reliable and useful means of locating the DG and PP.

Partition-based mass clustering of tractography streamlines.

We describe a novel scalable clustering framework for streamlines obtained from diffusion tractography. Clustering is an attractive means of segmenting a large set of streamlines into anatomically relevant bundles. For most existing methods, however, the large datasets produced in high resolution or multiple subject studies are problematical. To achieve good scalability, our method repeatedly divides the data into subsets, which are then partitioned using hierarchical clustering. A final partition is obtained by recombining the subsets. In addition, the recombination scheme provides a consistency measure for cluster assignment of individual streamlines, which is used to clean up the final result. The clusters have good anatomical plausibility and we show that three clusters corresponding to the three known segments of the arcuate fasciculus show excellent agreement with literature. A major advantage of the method is the fact that it can find clusters in datasets of essentially arbitrary size. This fact is exploited to find consistent clusters in concatenated tractography data from multiple subjects. We expect the identification of bundles across subjects to be an important application of the method.

Stratum radiatum of CA2 is an additional target of the perforant path in humans and monkeys.

The perforant path (PP) connects two key components of the medial temporal memory system, the entorhinal cortex and hippocampus. Entorhinal layer II projects densely to the outer portion of the molecular layer of the dentate gyrus and the stratum lacunosum-moleculare of CA2 and CA3 of the hippocampus. This study for the first time reports that the PP terminal zone originated from entorhinal layer II extends from the stratum lacunosum-moleculare into the stratum radiatum in CA2 but not in CA3 in both human and nonhuman primates. This result indicates that CA2 probably receives additional innervation from the PP compared with CA3 and thus may play a unique role in hippocampal memory networks.

Modulation of extracellular monoamine transmitter concentrations in the hippocampus after weak and strong tetanization of the perforant path in freely moving rats.

Hippocampal long-term potentiation (LTP) is considered as a cellular model of memory formation. Specific, electrical weak tetanization of distinct afferents such as the medial perforant path results in a short-lasting, protein synthesis-independent early-LTP (up to 4 h) within the dentate gyrus. A stronger tetanization leads to late-LTP (>4 h), which is protein synthesis-dependent and requires heterosynaptic activation during its induction, the latter of which can be provided by afferents from cortical brain regions or subcortical nuclei during memory formation in the behaving animal. In particular, noradrenaline (NA) is required for late-LTP in the dentate gyrus and dopamine for late-LTP in the apical CA1-dendrites. However, little is known about the concentrations and temporal dynamics of such neuromodulators like NA, serotonin (5-HT) and dopamine (DA) during LTP. We now implemented the microdialysis method to study this topic after stimulating the dentate gyrus in more detail. A weak tetanus of the perforant path, which normally leads to early-LTP, transiently but significantly decreased the concentration of NA (3 h) and increased the concentration of 5-HT (about 2 h) and DA (about 1 h) in the hippocampus. A strong tetanus, normally resulting in late-LTP, increased concentrations of NA and DA significantly and long-lasting (for about 5 h), whereas 5-HT concentration was increased with a delay (after about 30 min) and only for a short time (30 min). Thus different stimulation protocols resulted in different release patterns of neuromodulators, that may support discriminative processing of incoming information in the hippocampus.

Stimulation of basolateral amygdaloid serotonin 5-HT(2C) receptors promotes the induction of long-term potentiation in the dentate gyrus of anesthetized rats.

We have previously found that the induction of hippocampal long-term potentiation (LTP) is modulated by neuron activities in the basolateral amygdala (BLA). However, little is known about what neurotransmitter system in the BLA contributes to modulation of hippocampal LTP. In the present study, we investigated possible involvement of BLA serotonergic system in the induction of LTP at the perforant path (PP)-dentate gyrus (DG) granule cell synapses of anesthetized rats. The induction of PP-DG LTP was significantly inhibited by intra-BLA injection of the 5-HT(2) receptor antagonist cinanserin (25-50nmol), but not by intra-BLA injection of the 5-HT(1,7) receptor antagonist methiothepin (50nmol), the 5-HT(3) receptor antagonist ondansetron (50nmol) or the 5-HT(4) receptor antagonist RS23597-190 (100nmol). In addition, intra-BLA injection of the 5-HT(2C) receptor agonist MK212 (50nmol) facilitated the induction of PP-DG LTP. These results suggest that the induction of PP-DG LTP is promoted by activation of 5-HT(2C) receptors in the BLA.

The CB1 receptor antagonist, SR141716A, prevents high-frequency stimulation-induced reduction of feedback inhibition in the rat dentate gyrus following perforant path stimulation in vivo.

Endocannabinoids acting through CB(1) receptors are thought to regulate GABAergic and glutamatergic neurotransmission and may modulate long-term potentiation (LTP). High-frequency stimulation (HFS) of the medial perforant path to induce LTP was studied in the dentate gyrus with or without the selective CB(1) receptor antagonist, SR141716A in isoflurane-anaesthetised rats. HFS significantly increased the slope of the field excitatory post-synaptic potential (fEPSP) and the amplitude of the population spike (PS; P<0.001 in each case; n=6). Following administration of SR141716A, HFS no longer increased fEPSP slope, whereas PS amplitude potentiation remained significant (P<0.0001; n=6). Paired-stimuli revealed that HFS significantly reduced inhibition observed at intervals of 10 ms (P<0.01; n=6), and produced a leftward shift of the interval-inhibition curve (P<0.05; n=6). Following administration of SR141716A, HFS no longer reduced inhibition at the 10 ms interval, but a leftward shift in the interval-inhibition curve was still observed (P<0.05, n=6). These results indicate that LTP in the dentate gyrus reduces local circuit inhibition, consistent with a reduction of GABA release and/or duration of the post-synaptic GABA-receptor mediated response. Selective effects of SR141716A on the degree, but not the timecourse, of paired-pulse inhibition suggest that the reduction in GABA release following LTP induction is due to CB(1) activation. Results also suggest that CB(1) receptors contribute to HFS-induced potentiation of the fEPSP, but not to the mechanism underlying potentiation of PS amplitude. We suggest that CB(1) activation during HFS of the medial perforant path increases glutamate release from perforant path synapses, but inhibits release of GABA from local circuit interneurons.

The perforant path: projections from the entorhinal cortex to the dentate gyrus.

This paper provides a comprehensive description of the organization of projections from the entorhinal cortex to the dentate gyrus, which together with projections to other subfields of the hippocampal formation form the so-called perforant pathway. To this end, data that are primarily from anatomical studies in the rat will be summarized, complimented with comparative data from other species. The analysis of the organization of any of the connections of the hippocampus, including that of the entorhinal cortex to the dentate gyrus, is severely hampered because of the complex three-dimensional shape of the hippocampus. In particular in rodents, but to a lesser extent also in primates, all traditional planes of sectioning will result in sections that at some point or another do not cut through the hippocampus at an angle that is perpendicular to its long axis. To amend this, we will describe own unpublished tracing data obtained in the rat with the use of the so-called extended preparation. A number of issues will be addressed. First, data will be summarized which will clarify the laminar origin of the perforant pathway within the entorhinal cortex. Second, we will discuss whether or not a radial organization, along the proximo-distal dendritic axis of granule cells, characterizes the entorhinal-dentate projection. Third, we will discuss whether this projection is governed by any transverse organization, and fourth, we will focus on the organization along the longitudinal axis. Finally, the synaptic organization and the contralateral entorhinal-dentate projection will be described briefly. Taken together, the available data suggest that the projection from the entorhinal cortex to the dentate gyrus is a fairly well conserved connection, present in all species studied, exhibiting a grossly similar organization.

Dissociations of the medial and lateral perforant path projections into dorsal DG, CA3, and CA1 for spatial and nonspatial (visual object) information processing.

Medial perforant path plasticity can be attenuated by 2-amino-5-phosphonovaleric acid (APV) infusions, whereas lateral perforant path plasticity can be attenuated by naloxone infusions. The present experiment was designed to evaluate the role of each entorhinal efferent pathway into the dorsal hippocampus for detection of spatial and nonspatial (visual object) changes in the overall configuration of environmental stimuli. Dorsal dentate gyrus infusions of either APV or naloxone attenuated detection of a spatial change, whereas only naloxone infusions disrupted novel object detection. Either APV or naloxone infusions into dorsal CA3 disrupted both spatial and novel object detection. APV infusions into dorsal CA1 attenuated detection of a spatial change, whereas naloxone infusions into dorsal CA1 disrupted novel object detection. These data suggest that each dorsal hippocampal subregion processes spatial and nonspatial (visual object) information from perforant path efferents in a unique manner that is consistent with the intrinsic properties of each subregion.

MR features of the developing perianterior horn structure including subcallosal fasciculus in infants and children.

INTRODUCTION: To describe the changes in the magnetic resonance (MR) signal of the perianterior horn structure (PAS) with increasing age, we studied 69 infants and children aged between 3 days and 9.4 years (average: 2.8 years) without any neurological deficits. METHODS: T1- and T2-weighted images and FLAIR (fluid attenuation inversion recovery) images were obtained in the axial plane. Based on a comparison of the intensity of the PAS with that of the cortex in each sequence (T1-WI/FLAIR/T2-WI), we classified the signal-intensity patterns into four types: I, low/low/high; II, low/high/high; III, iso/high/high; IV, high/low/low. RESULTS: Signal-intensity types I, II, III and IV were seen in 22, 8, 17, and 22 subjects, respectively, with younger subjects showing type I or II intensity patterns and older subjects showing type III or IV. In addition, T1-weighted and FLAIR images of subjects with a type I intensity pattern showed a rim of an isointensity component around the PAS that histologically coincided with migrating glial cells. The low-intensity area on FLAIR and T2-WI images of subjects with a type IV intensity pattern may represent myelinated fibers of the subcallosal fasciculus (ScF). CONCLUSION: The intensity of the MR signals of the PAS changes with increasing age, and this change may reflect histological features. A better understanding of these characteristics may help us to clarify myelination abnormalities, particularly those related to the ScF in the frontal lobe in infants and children.

Associational sprouting in the mouse fascia dentata after entorhinal lesion in vitro.

Collateral sprouting is a form of neuronal plasticity observed in brain following injury. In order to establish an in vitro model of collateral sprouting, entorhino-hippocampal slice cultures were prepared from brain of C57BL/6 mouse pups (P1-4) and incubated for 14-16 days in vitro. Thereafter, entorhino-hippocampal fibers were cut and the outer molecular layer of the fascia dentata was denervated. At this age, entorhino-hippocampal fibers do not regenerate, as could be shown using anterograde tracing with Miniruby. Sprouting of associational mossy cell axons was monitored using calretinin-immunocytochemistry. Control and lesioned entorhino-hippocampal slices were studied at 1, 5, and 10 days postlesion. Whereas only the inner portion of the molecular layer was occupied by calretinin-positive mossy cell axons in controls and after 1 and 5 days postlesion, the entire width of the molecular layer was occupied by associational fibers by 10 days postlesion. Thus, robust sprouting of associational mossy cell axons occurs in response to entorhinal denervation in vitro. Using organotypic entorhino-hippocampal slices of genetically engineered mice, this sprouting model can be used to identify molecules involved in the regulation of sprouting following brain injury.

Anomalous asymmetry of fusiform and parahippocampal gyrus gray matter in schizophrenia: A postmortem study.

OBJECTIVE: Anomalies of structure and asymmetry of the parahippocampal gyrus (origin of the perforant path input to the hippocampal formation in the medial temporal lobe) have been shown in some postmortem studies of schizophrenia, but previous studies have not included the fusiform gyrus (which may have a role in facial recognition and naming), adjacent to the parahippocampal gyrus on the ventral occipitotemporal surface. METHOD: The volumes of gray matter in the left and right parahippocampal and fusiform gyri were assessed with a stereological point-counting technique in the temporal lobes from formalin-fixed brains of 27 comparison subjects and 31 patients with schizophrenia. Age was a covariate and gender was a factor in the analysis. RESULTS: In relation to the comparison subjects, the schizophrenic patients (both sexes) had lower volumes of both the parahippocampal and fusiform gyri on the left side. For both structures a left-greater-than-right volume asymmetry was present in the comparison subjects, but this asymmetry was reversed in the parahippocampal and fusiform gyri of the schizophrenic patients. A sex difference was present with respect to age at onset-degree of anomaly of asymmetry for both gyri increased with age at onset in men but not in women. CONCLUSIONS: The findings add substance to the view that the sex-related dimension of symmetry/asymmetry is integral to the disease process in schizophrenia and draw attention to the fusiform gyrus as a structure of particular interest in relation to disturbances of identification and naming in psychosis.

Brain-derived neurotrophic factor infusion delays amygdala and perforant path kindling without affecting paired-pulse measures of neuronal inhibition in adult rats.

Kindling is an animal model of human temporal lobe epilepsy in which excitability in limbic structures is permanently enhanced by repeated stimulations. Kindling also increases the expression of nerve growth factor, brain-derived neurotrophic factor, and brain-derived neurotrophic factor receptor messenger RNAs in both the hippocampus and cerebral cortex and causes structural changes in the hippocampus including hilar hypertrophy. We have recently shown that intraventricular nerve growth factor infusion enhances the development of kindling, whereas blocking nerve growth factor activity retards amygdaloid kindling. Furthermore, we have shown that nerve growth factor protects against kindling-induced hilar hypertrophy. The physiological role of brain-derived neurotrophic factor in kindling is not as clear. Acute injection of brain-derived neurotrophic factor increases neuronal excitability and causes seizures, whereas chronic brain-derived neurotrophic factor infusion in rats slows hippocampal kindling. In agreement with the latter, we show here that intrahilar brain-derived neurotrophic factor infusion delays amygdala and perforant path kindling. In addition, we show that brain-derived neurotrophic factor, unlike nerve growth factor, does not protect against kindling-induced increases in hilar area. To test the hypothesis that brain-derived neurotrophic factor suppresses kindling by increasing inhibition above normal levels, we performed paired-pulse measures in the perforant path-dentate gyrus pathway. Brain-derived neurotrophic factor infused into the hippocampus had no effect on the stimulus intensity function (input/output curves); there was also no significant effect on paired-pulse inhibition. We then kindled the perforant path 10 days after the end of brain-derived neurotrophic factor treatment. Once again, kindling was retarded, showing that the brain-derived neurotrophic factor effect is long-lasting. These results indicate that prolonged in vivo infusion of brain-derived neurotrophic factor reduces, rather than increases, excitability without increasing inhibitory neuron function, at least as assessed by paired-pulse protocols. This effect may be mediated by long-lasting effects on brain-derived neurotrophic factor receptor regulation.

Lesions of the medial or lateral perforant path have different effects on hippocampal contributions to place learning and on fear conditioning to context.

The axons of the neurons in the medial and lateral components of the entorhinal cortex (MEC and LEC) form the medial and lateral perforant paths (MPP and LPP) which represent the major source of cortical input to the hippocampus. Anatomical, physiological, and pharmacological studies have shown that MPP and LPP are distinct. Unfortunately, assessment of the functional significance of damage to either of these pathways has not used tasks known to be sensitive to hippocampal function in the rodent. In this study, we performed dissociated lesions of MPP and LPP using a combined physiological and anatomical method. Rats with lesions of either the MPP or the LPP were tested on place learning in the water task and on a discriminative fear conditioning to context task. The results indicated that the MPP, but not LPP, lesions resulted in impaired place learning. The context discrimination data revealed an amygdala-like, reduced fear effect of MPP lesions and an enhanced discriminative fear conditioning to context effect of LPP lesions. Consistent with a two-stage model of spatial learning proposed by Buzsaki (Buzsaki G. Two-stage model of memory trace formation: a role for 'noisy' brain states. Neuroscience 1989;31(3):551-570), the impairment in the water task can be interpreted as reflecting the higher efficiency of the MPP synapses in activating hippocampal neurons. The context discrimination results can be explained by either a dissociation of sensory information that reaches the MEC and LEC, or alternatively, by a dissociation between the limbic nature of the MEC and the sensory nature of the LEC.

Modelling recovery of cognitive function after traumatic brain injury: spatial navigation in the Morris water maze after complete or partial transections of the perforant path in rats.

The Morris water maze (MWM) has been used to assess cognitive function in rats after a variety of lesions designed to model brain damage and to assess the effects of drugs, growth factors, and neural transplants on post-operative deficits. The present study examined recovery of spatial navigation in the MWM over time in order to model the spontaneous recovery of cognitive function seen in humans. Diffuse axonal injury, a neuropathology commonly associated with traumatic brain injury (TBI), was modelled by transecting the perforant path (PP) bilaterally, either caudal to the hippocampus or dorsal to it at the decussation of the dorsal hippocampal commissure. Both groups with PP cuts showed substantial deficits initially, but spatial performance recovered with time and training. Recovery of platform finding was nearly complete within 14 days of testing, but recovery of platform searching did not occur for 2 or 3 more weeks. When the platform was moved to a new location, a continuing deficit in learning rate was revealed. When the platform was moved to a new position every day, this deficit was even more evident. These results illustrate the multi-faceted nature of recovery after brain injury and provide a new model for assessing the effects of manipulations designed to modulate recovery.

Cellular and molecular bases of memory: synaptic and neuronal plasticity.

Discoveries made during the past decade have greatly improved our understanding of how the nervous system functions. This review article examines the relation between memory and the cellular mechanisms of neuronal and synaptic plasticity in the central nervous system. Evidence indicating that activity-dependent short- and long-term changes in strength of synaptic transmission are important for memory processes is examined. Focus is placed on one model of synaptic plasticity called long-term potentiation, and its similarities with memory processes are illustrated. Recent studies show that the regulation of synaptic strength is bidirectional (e.g., synaptic potentiation or depression). Mechanisms involving intracellular signaling pathways that regulate synaptic strength are described, and the specific roles of calcium, protein kinases, protein phosphatases, and retrograde messengers are emphasized. Evidence suggests that changes in synaptic ultrastructure, dendritic ultrastructure, and neuronal gene expression may also contribute to mechanisms of synaptic plasticity. Also discussed are recent findings about postsynaptic mechanisms that regulate short-term synaptic facilitation and neuronal burst-pattern activity, as well as evidence about the subcellular location (presynaptic or postsynaptic) of mechanisms involved in long-term synaptic plasticity.