Changes In Synaptic Connectivity Research Articles

Neurobiological Investigations in Cingulate Cortex of Schizophrenic Brain

Several studies have indicated that the pathophysiology of schizophrenia may involve discrete alterations of intrinsic circuits within the anterior cingulate cortex, particularly in layer II. These findings have suggested the possibility that a disturbance in neuronal migration or differentiation during the perinatal period could be related to these differences in schizophrenia subjects. To explore the idea that schizophrenia may be a neurodevelopmental disorder in which precise changes in synaptic connectivity occur, model circuits can be used as empirical tools for identifying the nature and origin of layer II abnormalities in the cortex of schizophrenic brain. Eventually, a strategy of this type may point the way to novel treatment approaches that will limit or perhaps even prevent the deterioration that occurs in patients with schizophrenia.

Expression of the Neural Recognition Molecule L1 by Cultured Neural Cells is influenced by K+ and the Glutamate Receptor Agonist NMDA.

To investigate the influence of neuronal activity on the expression of neural recognition molecules, cultures of neural cell lines and dissociated cells of early postnatal mouse cerebellum were maintained in the presence of elevated concentrations of K+ and the glutamate agonist N-methyl-d-aspartate (NMDA). Levels of expression of the neural adhesion molecules L1 and N-CAM at the cell surface were measured by an enzyme-linked immunosorbent assay. Expression of L1 was up-regulated in neuroblastoma N2A cells after 1 day of maintenance in 40 and 60 mM K+, but not in phaeochromocytoma PC12 cells. Expression levels of N-CAM and antigens recognized by the monoclonal antibody A2B5 or by polyclonal antibodies to crude membrane fractions of liver were not significantly altered by elevated K+ concentrations in these two cell lines. In monolayer cultures of early postnatal mouse cerebellum, an increase of 60% in expression of L1, but not N-CAM or A2B5, was seen at 20 and 40 mM K+. This increase in L1 expression was specifically inhibitable by the Ca2+ channel blocker nicardipine. NMDA at a concentration of 100 microM increased levels of L1, but not of N-CAM. This increase was inhibitable by the NMDA antagonists 2-amino-5-phosphonovalerate and MK-801, but not significantly by the kainate/quisqualate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. The increase in L1 expression at higher K+ concentrations was not inhibitable by the NMDA antagonists, indicating that the K+-mediated increase in L1 expression is not due to release of glutamate by cerebellar neurons. These observations indicate that compounds influencing neuronal membrane properties, and thus neuronal excitability, are capable of regulating the expression of L1. In a more general context, these findings suggest that previously observed changes in synaptic connectivity in situ, resulting from activity-dependent fine tuning of neuronal morphology, may be mediated by alterations in the expression of recognition molecules.

Glycoproteins modulate changes in synaptic connectivity in memory formation.

Glycoproteins modulate changes in synaptic connectivity in memory formation.

Molecular Interactions Modulating Neuronal Survival and Growth

The extracellular environment of the neuron provides a heterogeneous milieu of survival and growth modulating molecular species subserving regulatory signals that operate in development, mediate activity-dependent enduring changes in synaptic connectivity, and promote or inhibit survival and axonal regeneration following insult. Parallel distributed processing networks in neurons, activated by these molecular species, can likely be recruited selectively to serve specific needs of the organism.

Roles of ATP and adenosine derivatives for frequency-dependent changes of synaptic connections, long-term potentiation(LTP) and long-term depression(LTD).

Roles of ATP and adenosine derivatives for frequency-dependent changes of synaptic connections, long-term potentiation(LTP) and long-term depression(LTD).

Intracellular neurophysiological analysis reveals alterations in excitation in striatal neurons in aged rats

Intracellular recordings were used to characterize the physiological changes underlying decreases in excitation observed in striatal neurons during the aging process. Rats were divided into 3 age groups: young (3–5 months), middle-aged (10–12 months) and aged (>24 months). All experiments were performed in urethane-anesthetized rats. Recordings were obtained from 33 neurons in young, 17 in middle-aged and 20 in aged rats. When identified by intracellular injections of Lucifer yellow all recorded neurons were medium-sized spiny cells. Resting membrane potentials were at least −40 mV and action potentials greater than 35 mV. Postsynaptic responses were evoked by stimulation of frontal cortex. In all recorded neurons, regardless of age, excitatory postsynaptic potentials (EPSPs) could be evoked. However, the threshold currents for eliciting both EPSPs and synaptically driven action potentials were significantly higher in neurons obtained from aged rats than those recorded in the other two groups. Other changes in excitation in aged striatal neurons consisted of absence of spontaneously occurring EPSPs, higher current to induce firing by intracellular injections of depolarizing current and an inability of orthodromically induced action potentials to follow paired stimulation pulses to the cortex at short interpulse intervals. These data were interpreted to indicate that a combination of changes in synaptic connectivity and in membrane properties underlie the decreases in excitation. Together with our previous findings obtained from aged cats these results indicate that decreased neuronal excitability is a major effect of aging in the striatum.

The refinement of invertebrate synapses during development.

Evidence is provided that during invertebrate development synapses undergo a period of refinement during which there are changes in synaptic connectivity and specific synaptic properties. It appears that extrinsic cues such as competition and neural activity are involved in guiding these synaptic changes in invertebrates. Comparisons are made with findings in the vertebrate literature.

Ketamine—xylazine anaesthesia blocks consolidation of ocular dominance changes in kitten visual cortex

In the visual cortex of mammals, response properties of single neurons can be changed by restricted visual experience during early postnatal development. Covering one eye for four to eight hours when kittens are at the peak of the sensitive period is sufficient to weaken the influence of the occluded eye on cortical neurons resulting in a noticeable shift of ocular dominance towards the open eye. The underlying changes in synaptic connections do not occur so readily when a kitten is anaesthetized and paralysed. We report here that an ocular dominance shift is prevented in alert kittens that receive repeated brief monocular exposures when these are followed by ketamine-xylazine anaesthesia. This retrograde effect on cortical plasticity suggests that the process by which synaptic activity is converted into structural changes has been disturbed.

Synapse elimination in neonatal rat muscle is sensitive to pattern of muscle use.

The synaptic connections among the cells of the vertebrate nervous system undergo extensive rearrangements early in development. During their initial growth, neurones apparently form synaptic connections with an excessive number of targets, later retracting a portion of these synapses in establishing the adult neural circuits. Because of the profound effects which experience has upon the developing nervous system, a question of considerable interest has been the role which the functional use of these developing synapses might play in determining the final pattern of connectivity. At the neuromuscular junction the early changes in synaptic connections are well documented, and here questions about the importance of function can be relatively easily addressed. Mammalian skeletal muscle fibres experience a perinatal period of synapse elimination so that all but one of several synapses formed on each muscle fibre are lost. This synapse elimination is sensitive to alterations of neuromuscular use or activity. Reduction of muscle use by tenotomy or by paralysis of the muscle with drugs blocking nerve impulse conduction or neuromuscular transmission delays or even prevents synapse loss, while increased use produced by stimulation of the muscle nerve apparently accelerates the rate at which synapses are lost. I report here a further examination of the role of neuromuscular activity in synapse elimination. I show that chronic neuromuscular stimulation accelerates synapse elimination but that this acceleration is dependent on the temporal pattern in which the stimuli are presented: brief stimulus trains containing 100 Hz bursts of stimuli produce this acceleration whereas the same number of stimuli presented continuously at 1 Hz do not. Furthermore, the 100 Hz activity pattern which is effective in altering synapse elimination also alters two other muscle properties: the sensitivity of the muscle fibers to acetylcholine and the 'speed' of muscle contractions. These findings suggest that the ability of muscle fibres to maintain more than one nerve terminal, like other muscle properties, is sensitive to the pattern of muscle use rather than just the total amount of use.

Changes in rubral multiunit activity after lesions in the interpositus nucleus of the cat

The initial effect of an acute lesion in the central nervous system is loss of neural function. With time, however, restorative processes, generally termed 'compensation', may result in some degree of recovery of neural function. The mechanisms involved in recovery may include morphological changes in synaptic connections, a process described as neuroplasticity. Direct evidence for neuroplasticity in the mature mammalian central nervous system has been presented (for recent reviews, see refs. 3-6). Electrophysiological studies of the rubrospinal tract in the cat have shown evidence of neuroplasticity in which sprouting of axonal terminals (collateral sprouting) is thought to occur in the red nucleus following partially deafferenting lesions ~4. The demonstration of synaptic reorganization in this nucleus is based on evidence that the two major inputs to this nucleus, corticorubral and interpositorubral fibers, make synaptic connection with two separate portions of the membranes of rubral neurons. Tsukahara and co-workers12, la showed in the intact cat that excitatory postsynaptic potentials (EPSPs) evoked in rubral neurons by stimulating the ipsilateral pericruciate cortex had relatively slow rise times, long decay phases, and low peak amplitudes. EPSPs evoked by stimulating the contralateral interpositus nucleus displayed more rapid rise times, shorter decay phases, and greater peak amplitudes. They attributed these differences to segregation of synaptic terminals on rubral neurons, cortical fibers on distal dendrites and interpositus fibers on proximal dendrites and somas. The reorganization of cortical synaptic contacts on rubral neurons after partial deafferenration was investigated in chronic cats with lesions of the contralateral interpositus nucleus 14. They observed a progressive shortening of the rise times of cortically evoked EPSPs for 4~10 days after the lesions and no further change after longer intervals. These changes in cortically evoked EPSPs were thought to result from collateral sprouting of cortical fibers to innervate more proximal portions of rubral neurons. If neuroplasticity participates in the recovery of motor function after a lesion, it must do so not only through changes in postsynaptic potentials, but also through changes in patterns of spike activity directed toward brain stem and spinal nuclei. It is not clear what effect changes in EPSP wave forms may have on rubral spike activity. We have investigated this issue by recording spontaneous multiunit spike activity in

Regeneration and changes in synaptic connections between individual nerve cells in the central nervous system of the leech.

The central nervous system of the leech has been used for the study of the formation of new synaptic connections by regenerating neurons. In control leeches, individual nerve cells in adjacent ganglia are connected in an orderly and stereotyped manner, with only little variation. In the present experiments, a bundle of axons running between two of the segmental ganglia has been severed and allowed to regenerate. Subsequently, the axons reestablish synaptic connections between certain identified nerve cells in the adjacent ganglia, selectively and accurately. Thus, individual sensory cells in one ganglion show a high degree of neural specificity in reestablishing cell to cell connections with a motor cell in the next ganglion. The performance of the regenerated synapses, however, is significantly altered in a consistent manner. The normal balance between the effects of inhibitory and excitatory innervation in leeches with regenerated synapses is different from that seen in normal leeches, with marked overemphasis on inhibition. Similar alterations have also been seen in a series of ganglia at a distance from the site of the lesion. After the operation, therefore, a widespread modification of synapses occurs along the length of the nerve cord.