Changes In Synaptic Activity Research Articles

Opposite changes in synaptic activity of organotypic rat spinal cord cultures after chronic block of AMPA/kainate or glycine and GABAA receptors.

1. The well-developed cytoarchitecture of rat organotypic spinal cord culture makes it a suitable model to explore how persistent suppression of certain synaptic inputs might be compensated by increased synaptic efficacy (homeostatic plasticity). 2. Spontaneous or electrically evoked synaptic transmission of patch-clamped ventral horn interneurons was studied in control solution after blocking, for the second week in culture, AMPA/kainate receptors with CNQX or glycine and GABAA receptors with strychnine and bicuculline, or indiscriminately removing inputs with tetrodotoxin (TTX). 3. In untreated cells, spontaneous postsynaptic currents (PSCs) had fast (tau < 5 ms) or slow (tau > 10 ms) decay. A similar separation was observed when recording miniature currents (mPSCs). Slow decay PSCs were suppressed by strychnine plus bicuculline while fast decay events were eliminated by CNQX. 4. After chronic CNQX treatment the frequency of spontaneous, fast PSCs (of larger amplitude) or mPSCs was almost doubled with respect to control. These events were blocked by acutely applied CNQX, which unmasked slow PSCs. 5. After chronic TTX treatment neither the frequency nor the amplitude of spontaneous events was changed. 6. After chronic strychnine and bicuculline treatment the frequency and amplitude of all PSCs was decreased in most cells. mPSCs were also decreased in frequency. Spontaneous or electrically evoked currents acquired a larger component mediated by NMDA receptor activity. 7. The developing spinal network thus operated distinct homeostatic processes which led to strong enhancement in glutamatergic transmission after CNQX block or to broad downregulation of synaptic activity following chronic exposure to strychnine and bicuculline.

Potential role of synaptopodin in spine motility by coupling actin to the spine apparatus

Dendritic spines are dynamic structures that rapidly remodel their shape and size. These morphological adaptations are regulated by changes in synaptic activity, and result from rearrangements of the postsynaptic cytoskeleton. A cytoskeletal molecule preferentially found in mature spines is the actin-associated protein synaptopodin. It is strongly expressed by spine-bearing neurons in the olfactory bulb, striatum, cerebral cortex, and hippocampus. In the hippocampus, principal cells express synaptopodin mRNA and sort the protein to the spine compartment. Within the spine microdomain, synaptopodin is preferentially located in the spine neck and is closely associated with the spine apparatus. On the basis of these data we hypothesize that synaptopodin could affect spine motility by bundling actin filaments in the spine neck. In addition, it could link the actin cytoskeleton of spines to intracellular calcium stores, i.e., the spine apparatus and the smooth endoplasmic reticulum.

Effects of prenatal alcohol exposure on the hippocampus: Spatial behavior, electrophysiology, and neuroanatomy

Prenatal exposure to alcohol can result in fetal alcohol syndrome (FAS), characterized by growth retardation, facial dysmorphologies, and a host of neurobehavioral impairments. Neurobehavioral effects in FAS, and in alcohol-related neurodevelopmental disorder, include poor learning and memory, attentional deficits, and motor dysfunction. Many of these behavioral deficits can be modeled in rodents. This paper reviews the literature suggesting that many fetal alcohol effects result, at least in part, from teratogenic effects of alcohol on the hippocampus. Neurobehavioral studies show that animals exposed prenatally to alcohol are impaired in many of the same spatial learning and memory tasks sensitive to hippocampal damage, including T-mazes, the Morris water maze, and the radial arm maze. Direct evidence for hippocampal involvement is provided by neuroanatomical studies of the hippocampus documenting reduced numbers of neurons, lower dendritic spine density on pyramidal neurons, and decreased morphological plasticity after environmental enrichment in rats exposed prenatally to alcohol. Electrophysiological studies also demonstrate changes in synaptic activity in in vitro hippocampal brain slices isolated from prenatal alcohol-exposed animals. Considered together, these observations demonstrate that prenatal exposure to alcohol can result in abnormal hippocampal development and function. Such studies provide a better understanding of neurological deficits associated with FAS in humans, and may also contribute to the development of strategies to ameliorate the effects of prenatal alcohol exposure on behavior. Hippocampus 2000;10:94–110. © 2000 Wiley-Liss, Inc.

Effects of prenatal alcohol exposure on the hippocampus: spatial behavior, electrophysiology, and neuroanatomy.

Prenatal exposure to alcohol can result in fetal alcohol syndrome (FAS), characterized by growth retardation, facial dysmorphologies, and a host of neurobehavioral impairments. Neurobehavioral effects in FAS, and in alcohol-related neurodevelopmental disorder, include poor learning and memory, attentional deficits, and motor dysfunction. Many of these behavioral deficits can be modeled in rodents. This paper reviews the literature suggesting that many fetal alcohol effects result, at least in part, from teratogenic effects of alcohol on the hippocampus. Neurobehavioral studies show that animals exposed prenatally to alcohol are impaired in many of the same spatial learning and memory tasks sensitive to hippocampal damage, including T-mazes, the Morris water maze, and the radial arm maze. Direct evidence for hippocampal involvement is provided by neuroanatomical studies of the hippocampus documenting reduced numbers of neurons, lower dendritic spine density on pyramidal neurons, and decreased morphological plasticity after environmental enrichment in rats exposed prenatally to alcohol. Electrophysiological studies also demonstrate changes in synaptic activity in in vitro hippocampal brain slices isolated from prenatal alcohol-exposed animals. Considered together, these observations demonstrate that prenatal exposure to alcohol can result in abnormal hippocampal development and function. Such studies provide a better understanding of neurological deficits associated with FAS in humans, and may also contribute to the development of strategies to ameliorate the effects of prenatal alcohol exposure on behavior.

Activity-dependent formation of perforated synapses in cultured hippocampal neurons.

The study investigated the formation of perforated synapses in rat hippocampal cell cultures. Perforated synapses are defined by their discontinuous postsynaptic densities (PSDs) and are believed to occur in parallel with changes in synaptic activity and possibly also synaptic efficacy. Several in vivo studies have demonstrated an increase in the frequency of perforated synapses induced by development and environmental stimulation as well as long-term potentiation (LTP). Also in in vitro brain slices, LTP was associated with an elevated number of perforated spine synapses. Our study demonstrated for the first time that the formation of perforated synapses can be induced by a short-term increase in spontaneous neural activity in a hippocampal cell culture model. Stimulation with the GABAA-antagonist picrotoxin (PTX) induced a significant increase in the percentage of perforated synapses. This strong increase was blocked when APV was added together with PTX, indicating that the formation of perforated synapses depended on the activation of NMDA receptors. We also showed that inhibition of the tissue type plasminogen activator (tPA-stop/PAI-1) significantly interfered with the activity-induced increase in perforated synapses. This implies that the proteolytic activities of tPA might be involved in steps which are downstream from the NMDA receptor-mediated synaptic plasticity leading to structural changes at synaptic contacts. In contrast, even long-term inhibition of electrical network activity by tetrodotoxin had no effect on the number of perforated synapses, but almost completely abolished the formation of spine synapses. These results indicate that a short-term increase in neural activity via NMDA receptors and a proteolytic cascade involving tPA lead to the formation of perforated synapses.

SYNAPTIC RESPONSES EVOKED BY LOWER URINARY TRACT STIMULATION IN SUPERIOR CERVICAL GANGLION CELLS IN THE RAT

Stimulation of afferent neurons from the urinary tract can evoke powerful cardiovascular reflexes in animals and in humans. Here we tested whether and to what extent postganglionic sympathetic neurons projecting to the head and neck are involved in these reflexes. In adult anesthetized female Wistar rats, reflex changes in synaptic activity elicited from the lower urinary tract were recorded in neurons of the superior cervical ganglion using intracellular recording techniques. Gentle movements of the urethral cannula and/or slow injections of 0.3 to 0.6 ml. saline into the bladder modified synaptic activity in 75% of neurons tested: 11/15 neurons tested showed reflexes to urethral stimulation (8 excitatory, 3 inhibitory) and 8/12 neurons responded to bladder distension (5 excitatory, 3 inhibitory). Five neurons showed a reciprocal response pattern to the two stimuli. Suprathreshold and subthreshold inputs to a given cell mostly showed the same type of response. There was no evidence that urinary tract stimulation recruited preganglionic inputs that did not have ongoing activity prior to the stimulus. Reflexes from the lower urinary tract clearly reached sympathetic neurons located in remote segments. The response incidence in the population studied suggests that most sympathetic neurons involved in cardiovascular regulation participate in these reflexes. The different reflex patterns probably occur in neurons with different functional targets in the head and neck.

Differential induction of c-Fos, c-Jun and Jun B in the rat central nervous system following unilateral entorhinal cortex lesion

In order to identify some of the molecular mechanisms that occur after a central nervous system trauma, the immediate early gene encoded proteins c-Fos, c-Jun and Jun B were analysed by immunocytochemistry following unilateral entorhinal cortex lesion (controls, 30 min, 2, 5, 12 and 24 h, two, six, 10 and 14 days, four weeks and six months postlesion). In the dentate gyrus, c-Fos was induced in some supragranular neurons (30 min), massively expressed in granule cells ipsilaterally to the lesion (2 h), expressed in hilar neurons (5 h and two days) and was absent at all later stages. A basal expression of c-Jun was found in dentate granule cells of controls, which was strongly increased on the lesion side (2 h) and on the side contralateral to the lesion (12 h). c-Jun expression returned to control levels by 24 h. Jun B was induced in granule cells ipsilateral to the lesion within 2 h and was back to control levels by 5 h. In the lateral septal area, c-Fos and c-Jun were induced 30 min postlesion and decreased rapidly thereafter. In the cerebral cortex, a widespread induction of c-Fos and c-Jun occurred within 30 min after entorhinal cortex lesion and this up-regulation lasted until two days postlesion. These data indicate that electrolytic lesion of the entorhinal cortex leads to a rapid and widespread induction of c-Fos, c-Jun and Jun B. Within the denervated fascia dentata, some of these changes may be linked to the reorganization processes following the lesion. Alternatively, the alterations in immediate early gene expression reported here may to be due to changes in synaptic activity or postlesional seizures which occur in this lesioning paradigm.

Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons.

Many excitatory synapses are thought to be postsynaptically 'silent', possessing functional NMDA but lacking functional AMPA glutamate receptors. The acquisition of AMPA receptors at silent synapses may be important in synaptic plasticity and neuronal development. Here we characterize a possible morphological correlate of silent synapses in cultured hippocampal neurons. Initially, most excitatory synapses contained NMDA receptors, but only a few contained detectable AMPA receptors. Synapses progressively acquired AMPA receptors as the cultures matured. AMPA receptor blockade increased the number, size and fluorescent intensity of AMPA receptor clusters and rapidly induced the appearance of AMPA receptors at 'silent' synapses. In contrast, NMDA receptor blockade increased the size, intensity and number of NMDA receptor clusters and decreased the number of AMPA receptor clusters, resulting in an increase in the proportion of 'silent' synapses. These results suggest that the number of silent synapses is regulated during development and by changes in synaptic activity.

Cocaine-induced changes in glutamate and GABA immunolabeling within rat habenula and nucleus accumbens.

We previously reported that subchronic administration of cocaine for 5 days via slow-release pellets results in pronounced degeneration in the lateral habenula (LHB) and its primary efferent tract, the fasciculus retroflexus [Ellison (1992): Brain Res 598:353-356; Ellison and Switzer (1993): Neuroreport 5:17-20]. The lateral habenula receives both GABA and glutamate afferents. In order to test the hypothesis that the cocaine-induced degeneration of the fasciculus retroflexus may be related to changes in synaptic activity of either GABA or glutamate nerve terminals within the LHB, the density of nerve terminal immunolabeling of either neurotransmitter was quantified after 5 days of chronic drug administration followed by either 1 or 14 days off the drug. The shell of the nucleus accumbens (NACs) was also analyzed, since this area is thought to be associated with the reward aspects of addictive stimulant drug administration and was previously shown not to be associated with fiber degeneration. We found that cocaine treatment resulted in a significant decrease in the density of nerve-terminal GABA immunolabeling located within the LHB in animals taken off the drug for either 1 or 14 days, while there was no change in the density of glutamate immunolabeling. In the NACs, there was a decrease in the density of glutamate immunolabeling within nerve terminals 1 day but not 14 days after cocaine administration. There was no change in the density of GABA immunolabeling within the NACs following the 1 or 14 day-off period. These results suggest that there are long-term changes in the density of GABA immunolabeling within the LHB and that the effects seen in glutamate synapses within the NACs are transitory. The long-term decrease in GABA immunolabeling within the LHB is consistent with the hypothesis that a decrease in inhibitory synaptic activity, leading to increased excitatory influence on LHB neurons, may result in neurotoxicity and the subsequent degeneration of the fasciculus retroflexus.

Effects of Healthy Aging on the Regional Cerebral Metabolic Rate of Glucose Assessed with Statistical Parametric Mapping

The aging process is thought to result in changes in synaptic activity reflecting both functional and structural cell derangement. However, previous PET reports on age-related changes in resting brain glucose utilization (CMRglc) have been discrepant, presumably because of methodological as well as subject screening differences. In contrast to other studies, which used a region of interest approach, the objective of the present work was to determine, by means of the SPM software, the changes in regional CMRglc as a function of age in 24 optimally healthy, unmedicated volunteers of ages from 20 to 67 years. Global CMRglc showed a significant decline with age (∼6% per decade,P<0.05), which concerned all the voxels studied save for most of the occipital cortex and part of the cerebellum. The most significant effects (P<0.001) concerned the association neocortex in perisylvian temporo-parietal and anterior temporal areas, the insula, the inferior and posterior-lateral frontal regions, the anterior cingulate cortex, the head of caudate nucleus, and the anterior thalamus, in a bilateral and essentially symmetrical fashion. The high posterior parietal cortex was not sampled in this study. This distribution of changes in CMRglc with age may differ from that seen in Alzheimer' disease, where the earliest metabolic reduction has been shown to affect the posterior cingulate cortex.

Modulation of levodopa-induced motor response complications by NMDA antagonists in Parkinson's disease

The complex dopamine-glutamate interactions within the basal ganglia are disrupted by chronic nigrostriatal denervation and standard replacement therapy with levodopa. Acute N-methyl- d-aspartate (NMDA) receptor blockade is able to overcome the changes in dopamine D 1- and D 2-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-lesioned rats. Preliminary results further suggest that NMDA receptor blockade can counteract levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primates and parkinsonian patients without substantially altering the motor benefit derived from levodopa. These results appear to be in accordance with our 2-deoxyglucose studies in 6-hydroxydopamine-lesioned rats showing that NMDA receptor blockade can attenuate many of the changes in synaptic activity induced by levodopa, particularly in the striatopallidal complex. Taken together, our observations suggest that abnormal glutamate transmission or dysregulation of NMDA receptor-mediated mechanisms contribute to levodopa-induced motor response complications. Additional preclinical and clinical experiments need to be completed with well tolerated glutamate antagonists to determine the full potential of glutamate receptor blockade as a long-term strategy against levodopa-related motor response complications in Parkinson's disease.

The effect of short periods of monocular deprivation on excitatory transmission in the striate cortex of kittens: a current source density analysis.

The goal of this study was to assess changes in synaptic activity in the visual cortex of kittens following brief periods of monocular deprivation. Field potentials evoked by electrical stimulation of both optic nerves were registered in vertical penetrations through areas 17 and 18 of 4-5 week-old kittens which had been monocularly deprived for 2-7 days. In order to assess the laminar distribution of synaptic currents these field potentials were subjected to a current source density analysis. Current source density profiles elicited from the deprived eye differed from those induced from the normal eye in several respects: 1) The amplitudes of the responses showed considerable variation at different recording sites across the tangential dimension of cortex. 2) On the average, sinks and sources were markedly reduced, and this reduction was relatively more pronounced in non-granular than in granular layers. 3) However, in 30% of the tracks the layer IV sink showed no attenuation. It was reduced in 48% of the tracks and completely suppressed in 22% of the tracks. These results indicate that a substantial fraction of the deprived thalamocortical synapses remained functional, but that many of these synaptic events remained subthreshold. The significance of these findings is discussed in the context of recovery processes following reverse suture.

Acetylcholine release at identified nerve terminals in the organ‐cultured frog neuromuscular preparation.

1. The frog cutaneous pectoris neuromuscular preparation was maintained in organ culture for a few days, at either 24 or 14 degrees C. The synaptic activity of identified nerve terminals was repeatedly examined in order to describe the sequence and time course of changes from normal synaptic activity to a complete synaptic silence. 2. We found that the 'transient stage' (stage II, according to Ko, 1981) consists of at least three distinct periods each characterized by a unique trend of change in synaptic activity. The initial change involved a simultaneous decay of both spontaneous and nerve stimulation-evoked release of acetylcholine (sub-stage II1). Subsequently, the frequency of spontaneous miniature endplate potentials (MEPPs) increased gradually, while the evoked release continued its monotonous decay (sub-stage II2). During the third sub-stage spontaneous MEPPs, but no evoked endplate potentials (EPPs), were observed (sub-stage II3). 3. Statistical properties of acetylcholine release in still-transmitting junctions at sub-stage II2 and in non-transmitting junctions at sub-stage II3 were investigated. MEPPs with skewed amplitude histograms and bursting behaviour were evident at both sub-stages. However, the incidence and the extent of these distortions were higher in the non-transmitting junctions. 4. An inverse relation between the quantal content of evoked release and the rate of spontaneous secretion was found in the transmitting junctions. 5. These results suggest that some of the deterioration of synaptic activity in organ culture is caused by an impairment of the release process itself. Possible cellular mechanisms are discussed.

Subcortical changes in the regional uptake of [3H]-2-deoxyglucose in the brain of the monkey during experimental choreiform dyskinesia elicited by injection of a gamma-aminobutyric acid antagonist into the subthalamic nucleus.

Hemichorea/hemiballismus was induced in monkeys by localized injections of a gamma-aminobutyric acid antagonist into the contralateral subthalamic nucleus. During active dyskinesia, [3H]-2-deoxyglucose was administered and, subsequently, regional cerebral metabolic activity was examined by autoradiographic exposure of brain sections. The results indicate that during dyskinesia there was an overall decrease in local cerebral glucose utilization in a number of structures on the side of the brain contralateral to the abnormal movements (ipsilateral to the drug injection). These structures included the injected subthalamic nucleus, both medial and lateral segments of the globus pallidus, the substantia nigra, and the ventral anterior and ventral lateral nuclei of the thalamus. On the basis of evidence that changes in the energy requirement of neurons are due mainly to changes in synaptic activity, the autoradiographic findings are interpreted as indicating that during experimental hemichorea/hemiballismus there was an overall decrease in synaptic activity of subthalamopallidal, subthalamonigral and pallidothalamic pathways on the side of the brain contralateral to the dyskinesia. This interpretation is discussed in relation to current theories of the pathophysiology of choreiform dyskinesias.

?-adrenergic receptor regulation and antidepressants: The influence of adrenocorticotropin

Chronic administration of antidepressants reduces brain beta-adrenergic receptor number and function. Peptide and steroid hormones are also capable of modifying receptor activity, and because circulating levels of these substances are altered in depressed patients, studies have been undertaken to determine whether hormones influence the neurochemical responses to antidepressant drugs. Co-administration of adrenocorticotropin (ACTH) and imipramine induces a more rapid reduction in brain beta-adrenergic receptor binding than is observed with either substance alone. Moreover, by itself, ACTH treatment alters the ability of norepinephrine to stimulate cAMP accumulation in brain tissue without affecting recognition site number. Lesioning of the dorsal noradrenergic bundle blocks the decline in beta-receptor number and activity produced by the ACTH-imipramine treatment. Indeed, administration of ACTH facilitated these increase in beta-receptor number that occurs following denervation. These data indicate that ACTH treatment influences beta-adrenergic receptor adaptations that occur in response to a change in synaptic activity. Such findings have implications in regard to the clinical responses to antidepressants, and the role of hormones in the etiology of affective illness.

Analysis of the habituation-like changes in transmission in the temporodentate pathway of the rat

Habituation-like decrements in extracellular measures of synaptic activation (population EPSP) and cell discharge (population spike) were analyzed in the dentate gyrus of the rat following repetitive low-frequency stimulation of the medial and lateral entorhinal cortex. Stimulation of either subdivision of the entorhinal projection system resulted in comparable habituation-like response decrements with similar stimulation regimens. However, habituating stimulation of one subdivision did not result in decreased responsiveness to stimulation of the other. Repetitive low-frequency stimulation or even a single pulse delivered to either subdivision did, however, result in a potentiation of granule cell discharge in response to stimulation of the other subdivision (a form of heterosynaptic potentiation). This heterosynaptic potentiation of granule cell discharge was not accompanied by any increase in the extracellular EPSP. Comparisons of the relationship between the population EPSP and population spike before and during habituating stimulation revealed changes in cell discharge in response to the habituating stimulus which could not be accounted for by changes in synaptic activation alone. The results suggest that repetitive activation of the temporodentate pathway alters granule cell output as a result of two processes, a habituation-like decrement in synaptic activation, and a potentiation of granule cell discharge as a consequence of prior activation.

Synaptic plasticity in the hippocampus

For many years part of the limbic system, the hippocampus, has been associated with memory. The discovery of cooperativity in the nerve fibres of this part of the brain, where long-term potentiation of synaptic transmission can be brought about by short-term changes in synaptic activity, now provides a possible physiological basis for at least some learning processes. Tim Bliss summarizes in this article our present knowledge in this area.

Action of some surfactants on neuromuscular transmission in frogs

The effect of bile salts, saponin, and Tween-80 on miniature end-plate potentials and electrotonic potentials of frog muscle fibers was studied. During the action of bile salts in a concentration of 10−4 g/ml the frequency of the synaptic potentials rose sharply. Their amplitude also increased. The input resistance of the muscle fiber decreased during the action of these substances. With an increase in their concentration to 10−3 g/ml bile salts caused an initial increase in frequency of the spontaneous synaptic potentials followed by their depression and complete disappearance. Tween-80 caused no appreciable change in synaptic activity, whereas saponin inhibited it. Lowering the external calcium ion concentration by two to eight times had no influence on the stimulating effect of bile salts, but the total removal of calcium reduced it. The substances tested stimulated secretion of acetylcholine from the nerve endings, probably through changes caused in the structure of the presynaptic membrane.

Dynamic aspects of synaptic ultrastructure: The Schloss Hardenberg lecture presented at the 4th annual meeting of the European brain and behavior society, Göttingen, 14 September 1972

The concept of the ‘presynaptic vesicular grid’ is briefly developed. It was postulated previously that this structure may have dynamic properties and that structural changes may be associated with changes in synaptic activity. Recent findings especially with the aid of the freeze etching method have demonstrated specific features of the presynaptic membrane that may be correlated with transmitter release. These features are far more pronounced in unanesthetized as compared with anesthetized preparations. Size and shape of the presynaptic vesicular grid may represent additional criteria of synaptic activity, although, direct evidence is still incomplete. The functional significance of the synaptic vesicular grid is mainly seen in the context of transient events. Nevertheless, longer lasting mechanisms, e.g., synaptic facilitation and potentiation may also be considered.