Regeneration of dopaminergic function in 6-hydroxydopamine-lesioned rats by neuroimmunophilin ligand treatment.

Nonimmunosuppressant immunophilin ligands have been found previously to stimulate neurite growth in culture and to promote regeneration of peripheral and central nerve fibers in vivo. To further characterize the effectiveness of these ligands, we have investigated the effect of the immunophilin ligand GPI-1046 in 6-hydroxydopamine (6-OHDA)-lesioned rats. In unlesioned rats, tetanic stimulation of the white matter induced long-term potentiation (LTP) of corticostriatal synaptic transmission as indicated by a 40-100% increase in the field potential amplitudes recorded in striatal brain slices. Unilateral microinjection of 6-OHDA into the substantia nigra resulted in a loss of corticostriatal LTP and in significant abnormality of motor behavior as assessed by amphetamine-induced ipsilateral rotations. Daily treatment of 6-OHDA-lesioned rats with GPI-1046 (10 mg/kg, s.c.) for 1 week reduced amphetamine-induced rotations by 75% and greatly restored the striatal tyrosine hydroxylase immunostaining. In addition, GPI-1046 almost completely restored corticostriatal LTP in 6-OHDA-lesioned animals. LTP in normal animals and that restored by GPI-1046 in lesioned animals were both blocked by the NMDA receptor antagonist APV, suggesting mediation by NMDA receptors. Both LTPs were sensitive to dopamine (DA) receptor antagonists. The nonselective DA receptor antagonist chlorpromazine and the selective D1-D5 receptor antagonist SCH23390 reduced the LTP by 90%. These results demonstrate that the immunophilin ligand GPI-1046 can reverse the abnormalities in the substantia nigra-striatal dopaminergic system that are caused by 6-OHDA, thus providing a potential therapeutic agent for Parkinson's disease.

Role of inhibition in cortical reorganization of the adult raccoon revealed by microiontophoretic blockade of GABA(A) receptors.

Cortical reorganization was induced by amputation of the 4th digit in 11 adult raccoons. Animals were studied at various intervals, ranging from 2 to 37 wk, after amputation. Recordings were made from a total of 129 neurons in the deafferented cortical region using multibarrel micropipettes. Several types of receptive fields were described in reorganized cortex: restricted fields were similar in size to the normal receptive fields in nonamputated animals; multi-regional fields included sensitive regions on both adjacent digits and/or the underlying palm and were either continuous over the entire field or consisted of split fields. The proportion of neurons with restricted fields increased with time after amputation and was greater than previously found in subcortical regions. A GABA(A) receptor antagonist (bicuculline methiodide), glutamate, and GABA were administered iontophoretically to these neurons while determining their receptive fields and thresholds. Bicuculline administration resulted in expansion of the receptive field in 60% of the 93 neurons with cutaneous fields. In most cases (33 neurons) this consisted of a simple expansion around the borders of the predrug receptive field, and the average expansion (426%) was not different from that seen in nonamputated animals. In some neurons (n = 4), bicuculline produced an expansion from one digit onto the adjacent palm or another digit, an effect never seen in control animals. Bicuculline also changed the split fields of seven neurons into continuous fields by exposing a responsive region between the split fields. Finally, bicuculline changed the internal receptive field organization of 10 neurons by revealing subfields with reduced thresholds. In contrast to the situation in nonamputated animals, iontophoretic administration of glutamate also produced receptive field expansion in some neurons (n = 6), but the size and/or shape of the change was different from that produced by bicuculline, indicating that the effects of bicuculline were not due to an overall facilitation of neuronal activity. These results are consistent with the hypotheses that an important component of long-term cortical reorganization is the gradual reduction in effective receptive field size and that intracortical inhibitory networks are partially responsible for these changes.

Effect of the glycine modulatory site of the N-methyl-D-aspartate receptor on synaptic responses in kitten visual cortex.

In visual cortical slices taken from kittens, the administration of D-serine, an agonist of the N-methyl-D-aspartate receptor complex, significantly enhanced synaptically evoked responses using field potential recordings in lower layer II/III. Expression of normally appearing long-term potentiation (LTP) took place in the presence of the agonist during high-frequency stimulation (HFS). The administration of an antagonist of this receptor, 7-chloro-kynurenic acid (7-Cl KY) alone had no appreciable effect on low-frequency synaptic transmission while HFS failed to induce LTP. Combined administration of D-serine and 7-Cl KY resulted in no alteration of low-frequency synaptic transmission, although expression of LTP was normally obtained. These results suggest that in visual cortex of kittens, the availability of this glycine binding site of the NMDA receptor is necessary for the expression of LTP.

Expansion of receptive fields in raccoon somatosensory cortex in vivo by GABA(A) receptor antagonism: implications for cortical reorganization.

The effect of antagonism of GABA(A) receptors on the receptive fields of raccoon primary somatosensory cortical neurons was tested using microiontophoretic administration of bicuculline methiodide (BMI). The size of cutaneous receptive fields was examined using minimal suprathreshold mechanical stimulation before, during, and after BMI administration. In 65 of 102 rapidly adapting neurons, BMI produced a clear expansion of the receptive field. The mean increase in receptive-field size was 286%. The receptive fields on the distal digit, which were initially smaller, showed smaller increases in absolute area than more proximal receptive fields, but the percentage increase did not vary with location. Greater expansion was seen in superficially located neurons than in those below 800 microm. Of particular significance was the finding that the expansion of receptive fields produced by BMI never extended from one digit onto an adjacent digit or onto the palm, even when the original receptive field was at the base of a digit. This finding indicates that intracortical GABAergic inhibition is insufficient to explain cortical reorganization following digit amputation.

Ultrastructural organization of transmitters in the cat lateralis medialis-suprageniculate nucleus of the thalamus: an immunohistochemical study.

The lateralis medialis-suprageniculate nuclear (LM-Sg) complex of the cat's posterior thalamus receives a rather wide variety of inputs from diverse cortical and subcortical areas. Previous ultrastructural studies of this nucleus demonstrated the presence of four types of vesicle-containing profiles and characterized some of these as gamma-aminobutyric acid (GABA)-containing terminals (Norita and Katoh [1987] J. Comp. Neurol. 263:54-67; Norita and Katoh [1988] Prog. Brain Res. 75:109-118). The present study has extended these observations by examining the immunoreactivity (ir) of LM-Sg, with antibodies raised against aspartate (Asp), glutamate (Glu), GABA, the acetylcholine (ACh) marker, choline acetyltransferase (ChAT), and substance P (SP), by using light and electron microscopy. Neuronal somata immunopositive for the excitatory amino acids (EAAs) Asp and Glu, were of medium size. EAA-ir terminals also were of medium size and contained round synaptic vesicles; they made asymmetrical synaptic contacts with dendritic profiles. Neuronal somata immunopositive for GABA were small. GABA-positive terminals also were small and contained pleomorphic synaptic vesicles; they formed symmetrical synaptic contacts with dendritic profiles. No neurons immunolabeled for ChAT were found. Terminals immunopositive for ChAT were small and contained round synaptic vesicles; these made symmetrical synaptic contacts, asymmetrical synaptic contacts, or both, of the en passant type with dendritic profiles. SP-immunolabeled neuronal somata were not found. Immunolabeled terminals were small, contained round synaptic vesicles, and made asymmetrical synaptic contacts with dendritic profiles. ChAT-ir and SP-ir axon terminals were not expressed evenly within LM-Sg. This difference in distribution suggests that within the LM-Sg, there may be a difference in specific sensory processing functions which correlate with transmitter type.

Metabotropic glutamate receptor 2/3 immunoreactivity in the developing rat cerebellar cortex.

In adult rat cerebellar cortex, the metabotropic glutamate receptors (mGluRs) 2 and 3 (mGluR2/3) are present in somata, dendrites, and terminals of Golgi cells as well as in presumed glial processes (Ohishi et al. [1994], Neuron 13:55-66). In the present study, spatiotemporal changes in immunostaining for mGluR2/3 were examined in postnatal rat cerebellar cortex. mGluR2/3-immunoreactive Golgi cell somata appeared first in the internal granular layer at postnatal day 3 (P3) and were restricted to lobules IX and X; however, by P5, they were present in all lobules. Immunoreactive Golgi cell axons were adult-like, appearing as tortuous fibers with clusters of varicosities. They were observed first in the internal granular layer at P7 and increased in number and complexity with time. It was confirmed that mGluR2/3-immunoreactive Golgi cell axon terminals belong to the synaptic glomerulus by P10. Immunoreactive Golgi cell dendrites extending into the molecular layer became prominent after P15. By that time, the immunostaining pattern was characteristic of Golgi cells, as seen typically in adults. Many intensely immunoreactive radial processes existed at birth (P0). These traversed the molecular and external granular layers, reaching the pial surface in every cerebellar lobule. Because they showed coimmunoreactivity for glial fibrillary acidic protein, they were confirmed to be Bergmann glial fibers. After P9, they began to lose immunoreactivity at the portion corresponding to the molecular layer, while an immunostained granular pattern appeared in that layer. Immunoreactive radial processes, however, remained in the external granular layer, and finally, at P21, they disappeared together along with the external granular layer. Granular staining in the molecular layer reached background levels at this time. These spatiotemporal changes in mGluR2/3 distribution suggested that there may be distinct roles for mGluR2/3 in Golgi cells and Bergmann glial cells during the early postnatal period. mGluR2/3 in Golgi cells might be associated closely with systemic maturation, whereas mGluR2/3 in Bergmann glia might be needed for neuron-glia interactions related to granule cell development.

Age-dependent, steroid-specific effects of oestrogen on long-term potentiation in rat hippocampal slices.

1. Long-term potentiation (LTP) of hippocampal population spike responses and excitatory postsynaptic potentials (EPSPs) from area CA1 stratum pyramidale was induced in slices of rat hippocampus maintained in vitro following brief high-frequency stimulation (HFS) of the Schaffer collateral-commissural pathway. When administered to slices prior to HFS, 17beta-oestradiol (OE2), at a concentration as low as 0.1 nM, suppressed the magnitude of the resultant HFS-induced potentiation in slices from prepubertal animals (3 and 4 weeks old) of both sexes. 2. OE2 did not suppress the induction of LTP in slices taken from the hippocampus of adult animals of either sex. 3. There was no similar suppressant effect of 17alpha-oestradiol (OE1), progesterone (PRG) or testosterone (TST) on LTP in the young animals, even at a concentration 100 times greater than was effective for OE2. 4. The anti-oestrogen compound tamoxifen (TMX; 1.0 and 10.0 microM), which acts principally at intracellular binding sites within the nucleus, was without effect in diminishing the suppressant effect of OE2 on LTP in slices from young animals. 5. The LTP observed in slices from both 3-week-old and adult rats was AP5 sensitive and thus was shown to be dependent on activation of NMDA receptors. Results from whole-cell recording experiments suggested that OE2 caused the LTP-suppressant effect through an action on NMDA-mediated currents. 6. These data suggest an age-dependent and possibly a surface membrane receptor-mediated role for oestrogens in modulating the efficacy of input-output properties of CA1 neurones produced by HFS during a critical period in development.

Projections from substantia nigra and zona incerta to the cat's nucleus of Darkschewitsch.

The goal of the present experiments was to examine the relationships of the nucleus of Darkschewitsch (ND) with the substantia nigra pars reticulata (SNr), the zona incerta (ZI), and the oculomotor nuclei by using wheat germ agglutinin-horseradish peroxidase (WGA-HRP) as a retrograde and anterograde neuronal tracer injected into various sites of the cat's brain. To eliminate the possibility that fibres of passage from the motor cortex passing through the SNr and ZI were responsible for the ND label, WGA-HRP also was injected into the SNr or the ZI after a large area of the frontal cortex, including the motor area, was destroyed. Retrograde axonal transport demonstrated that many cells of the rostromedial part of the ZI project to the ND, with the ipsilateral projections being dominant. Some cells of the caudomedial part of the SNr project to the ND, again, with the ipsilateral projection being dominant. A few small cells in the ND project bilaterally to the oculomotor nucleus. Anterograde tracer demonstrated that the SNr-ND terminal fields are less dense than the ZI-ND terminal fields. A few fine terminal fibres were observed bilaterally in the oculomotor, trochlear, and abducens nuclei. Electron microscopic examination demonstrated that these fine, labelled terminals contain pleomorphic vesicles and have symmetrical synaptic contacts with dendrites. These results indicate that the ND, a structure that is known to be important for the control of axial muscles (i.e., eye, head, and body muscles), is the target of projections from restricted areas of the SNr and ZI: areas that, during saccadic eye movement, may lead to disinhibition of the ND-oculomotor projection. Accordingly, the ND may function to inhibit the activity of extraocular muscles during saccades.

Subthreshold receptive fields and baseline excitability of "silent" S1 callosal neurons in awake rabbits: contributions of AMPA/kainate and NMDA receptors.

The contribution of NMDA and non-NMDA receptors to excitatory subthreshold receptive fields was examined in callosal efferent neurons (CC neurons) in primary somatosensory cortex of the fully awake rabbit. Only neurons showing no traditional (suprathreshold) receptive fields were examined. Subthreshold responses were examined by monitoring the thresholds of efferent neurons to juxtasomal current pulses (JSCPs) delivered through the recording microelectrode. Changes in threshold following a peripheral conditioning stimulus signify a subthreshold response. Using this method, excitatory postsynaptic potentials and inhibitory postsynaptic potentials are manifested as decreases and increases in JSCP threshold, respectively. NMDA and non-NMDA agonists and antagonists were administered iontophoretically via a multibarrel micropipette assembly attached to the recording/stimulating microelectrode. Receptor-selective doses of both AMPA/kainate and NMDA antagonists decreased the excitability of CC neurons in the absence of any peripheral stimulation. Threshold to JSCPs rose by a mean of 20% for both classes of antagonist. Despite the similar effects of NMDA and non-NMDA antagonists on baseline excitability, these antagonists had dramatically different effects on the subthreshold excitatory response to activation of the receptive field. Whereas receptor-selective doses of AMPA/kainate antagonists either eliminated or severely attenuated the subthreshold excitatory responses to peripheral stimulation, NMDA antagonists had little or no effect on the subthreshold evoked response.

Cholinergic innervation of the lateralis medialis-suprageniculate nuclear complex (LM-Sg) of the cat's thalamus: a double labeling immunohistochemical study.

The purpose of this study was to investigate morphological characteristics of the synaptic relations of choline acetyltransferase (ChAT)-positive terminals that are made with a variety of post-synaptic profiles in the lateralis medialis-suprageniculate nuclear complex (LM-Sg) using ChAT, gamma-aminobutyric acid (GABA) and glutamate immunohistochemistry in combination with electron microscopical observations. The ChAT immunopositive profiles make asymmetrical synaptic contacts with glutamate immunopositive dendrites that are presumably derived from projection neurons, and/or GABA immunopositive interneurons. The present results indicate that ascending cholinergic mechanisms may be important for modifying information in both the extrinsic and intrinsic circuitries of LM-Sg.

Antibodies to glutamate, aspartate and glycyl-D-aspartate reversibly suppress stimulus-evoked, extracellularly recorded responses in slices of rat neocortex.

Polyclonal antibodies raised against glutamate, aspartate and the dipeptide, glycyl-D-aspartate were dissolved in artificial cerebrospinal fluid (aCSF) and administered at concentrations as low as 0.05% to slices of prefrontal cortex maintained in vitro. These antisera caused a reversible attenuation of evoked field potentials and/or single-unit activity recorded extracellularly following the delivery of shocks to the underlying white matter, or to cortical layer IV. To the best of our knowledge, this result provides the first demonstration using electrophysiological recording of the use of a transmitter-specific antibody as a blocker of synaptic transmission in living slices of the central nervous system (CNS). The results lend support to the suggestion that glutamate, aspartate, and a molecule related closely to glycyl-D-aspartate, are involved in synaptic transmission at major pathways within prefrontal cortex.

Amino acids as the source of considerable excitation in cerebral cortex.

A number of different factors contributed to the rationale for providing a critical review of the field of excitatory amino acids in the cerebral cortex at this time. In addition to the recent growing realisation by clinicians that the excitatory amino acids are linked critically to a number of neurological conditions, including neurodegenerative syndromes such as Alzheimer's disease, cortical damage due to stroke and cerebral ischemia, epilepsy, amyotropic lateral sclerosis, and schizophrenia, the recent cloning and membrane reconstitution of specific receptors known as AMPA, NMDA, kainate, and metabotropic receptors and their known subunits have prompted a surge of renewed interest in this important family of synaptic transmitter molecules. Moreover, recent advances in our understanding of the molecular events involved in growth promotion in the early stages of the development of the cortex have shown that both NMDA and non-NMDA receptor subtypes perform important roles in certain aspects of target selection and neurite outgrowth, in cone stimulation and guidance, and in spine formation and morphological alterations. A recent explosive growth in interest in the possible roles of nitric oxide and related short-lived radicals in plasticity, disease, and synaptic transmission also is related closely with the actions of excitatory amino acids. All these relatively new advances have transpired in parallel with ongoing work that has extended our appreciation for the roles of excitatory amino acids in the areas of synaptic plasticity (long-term potentiation, long-term depression, receptive field reorganisation following drug-induced or peripheral sensory disturbances, such as denervation or amputation), in processes of normal transmission at functionally and electrophysiologically identified neurones of the cerebral cortex, and in distinct proposed roles for cortical glia. A greater appreciation of the diverse types and properties of the burgeoning family of receptors for the metabotropic receptor also contributed to our desire to feature that aspect of the field in the context of glia and neurones of the cerebral cortex. That part of the field of neuroscience concerned with the functions of excitatory amino acids has grown so large over the past 10 years or so, that a review paper focusing on the contributions to a specialized meeting devoted solely to cerebral cortex could easily be supported by material comprising a sufficient body of communications from top-quality research laboratories. The present account endeavours to summarize and discuss the biochemical characteristics, physiological roles, pharmacological properties, clinical relevance, developmental involvements, and anatomical-morphological aspects pertaining to the excitatory amino acid transmitters in cerebral cortex.

Somatosensory cortical efferent neurons of the awake rabbit: latencies to activation via supra--and subthreshold receptive fields.

1. Latencies to peripheral sensory stimulation were examined in four classes of antidromically identified efferent neurons in the primary somatosensory cortex (S1) of awake rabbits. Both suprathreshold responses (action potentials) and subthreshold responses were examined. Subthreshold responses were examined by monitoring the thresholds of efferent neurons to juxtasomal current pulses (JSCPs) delivered through the recording microelectrode (usually 1-3 microA). Through the use of this method, excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) were manifested as decreases and increases in threshold, respectively. Efferent populations examined included callosal (CC) neurons, ipsilateral corticocortical (C-IC) neurons, and descending corticofugal neurons of layer 5 (CF-5) and layer 6 (CF-6). Very brief air puffs (rise and fall times 0.6 ms) were delivered to the receptor periphery via a high-speed solenoid valve. 2. Whereas all CF-5 neurons had demonstrable suprathreshold excitatory and/or inhibitory responses to peripheral stimulation, most CC, C-IC, and CF-6 neurons did not. CC and CF-6 neurons that yielded no suprathreshold response to the stimulus had lower axonal conduction velocities than those that did respond (P < 0.0001 in both cases). However, subthreshold receptive fields could be demonstrated in many of the otherwise unresponsive CC (81%), C-IC (88%), and CF-6 (43%) neurons. The subthreshold responses usually consisted of an initial excitatory component (a decrease in the threshold to the JSCP) and a subsequent long-duration (> 80 ms) inhibitory component. A few neurons (1 CC, 1 C-IC, and 5 CF-6) showed an initial short latency inhibitory response in the absence of any excitatory component. 3. Some CC and C-IC neurons yielded supra- and/or subthreshold responses to peripheral stimulation at latencies of 6.1-7 ms. All such neurons were found at intermediate cortical depths (thought to correspond to deep layer 2-3 through layer 5). It is argued that such latencies are indicative of monosynaptic activation via thalamic afferents. Very superficial CC and C-IC neurons, and all CF-6 neurons responded to latencies of > 7 ms. All CF-5 neurons responded to latencies of > 8 ms, although many were found at the same depth as the deeper CC and C-IC neurons that responded at monosynaptic latencies. These results indicate that cortical cell type as well as laminar position are important factors that determine the sequence of intracortical neuronal activation after peripheral sensory stimulation.

A projection linking motor cortex with the LM-suprageniculate nuclear complex through the periaqueductal gray area which surrounds the nucleus of Darkschewitsch in the cat.

Whereas a previous study by one of us (Hicks et al., 1986) suggested that periaqueductal gray (PAG) neurons projecting to the lateralis medialis-suprageniculate (LM-SG) complex might mediate transmission of affective-related nociceptive information, our present work suggests instead, a function in processes related to movement. Cells of the nucleus of Darkschewitsch (ND) are known to have reciprocal projections with the motor cortex (MX), in particular with the hand area of MX, and also to project to the rostral medial accessory olivary (MAO) nucleus (Onodera and Hicks, 1995a). That the ND might be related to saccadic oculomotor function, as well as to the control of hand movements through its connections via the olivo-cerebellar circuit, is indicated by the fact that ND receives a strong projection from the substantia nigra pars reticulata and zona incerta (SNR/ZI) and projects directly and/or indirectly to eye movement nuclei (Onodera and Hicks, 1995b). Thus, ND may function in permitting integration of eye-hand motor coordination. This study focussed on the area of PAG surrounding ND. WGA-HRP was injected into MX and many labelled terminals and large neurones were in ND, with lesser numbers being observed in the area of the PAG surrounding ND. After injections into ND and closely adjacent areas, labelled terminals were observed sparsely distributed with a restricted area of the LM-SG complex. After injections into LM-SG area, small neuronal somata were seen in the area of the PAG surrounding ND, but no labelled somata were detected in ND. Thus if the cells of this PAG area, like those of ND, have similar functions owing to their common reciprocal connections with MX, then the small neurones in PAG projecting to LM-SG may constitute an important link in the circuitry subserving visual processing and/or the regulation of orienting movements of the hand, head and eye.

The effects of D-alpha-aminoadipic acid on long-term potentiation in the hippocampus of the rat in vitro.

Many studies on long-term potentiation (LTP) in hippocampal region CA1 focus on receptor-mediated events that are often presumed to be linked to postsynaptic processes. Whereas it is now well-known that LTP consists of multiple components involving increases in postsynaptic responsiveness as well as enhanced presynaptic release of transmitter, little specific information has accrued on the nature of the presynaptic receptor-linked events. In the course of a series of experiments examining the actions of several antagonists of N-methyl-D-aspartate (NMDA) receptors on LTP, we made certain observations that suggested the role of a novel type of amino acid receptor which possibly was located presynaptically and that seemed to contribute to the induction of LTP. LTP evoked in region CA1 following high frequency stimulation (HFS) of the Schaffer collateral-commissural pathway measured 20-30 min after HFS always was attenuated incompletely when induced during administration of DalphaAA at doses ranging from 50 mu M to as high as 1000 mu M, whereas 2-amino-5-phosphonopropionate (AP5), at a concentration of 30 mu M, always abolished the process completely. 6,7-Dinitroquinoxaline-2,3-dione (DNQX) (10 mu M) administered alone also did not block LTP completely unless delivered in combination with DalphaAA. These non-AP5-like effects of DalphaAA could not be attributed to incomplete antagonism of postsynaptic NMDA receptors, since DalphaAA (200 mu M) completely and reversibly blocked the membrane depolarising effects of NMDA, as assessed through intracellular recording. Furthermore, the pharmacologically isolated NMDA-receptor-mediated component of the low-frequency, stimulus-evoked synaptic response was always abolished reversibly by DalphaAA (200 mu M). The most parsimonious explanation of these data is that a receptor which is only activated during HFS, is sensitive to the antagonising actions of AP5 and possibly also to DNQX but not to DalphaAA, and which could conceivably exist on terminals of the Schaffer collateral-commissural fibres, makes a significant contribution to LTP.

Patterns of transmitter labelling and connectivity of the cat's nucleus of Darkschewitsch: a wheat germ agglutinin-horseradish peroxidase and immunocytochemical study at light and electron microscopical levels.

Immunocytochemical studies using antibodies raised against a number of probable synaptic transmitters of the mesodiencephalic area, and fibre-tracing studies using wheat germ agglutinin-horseradish peroxidase (WGA-HRP), have been performed in adult cats. Glutamate and aspartate immunoreactivity produced a strong labelling of many cell bodies and terminals in the nucleus of Darkschewitsch (ND). gamma-Aminobutyrate (GABA) immunoreactivity in the ND appeared as a moderate label in some small neurones, and as a strong label in a few glial-like cells, in addition to being present in high levels to produce strong labelling in many GABA-immunopositive terminals that possessed pleomorphic vesicles. Some choline acetyltransferase-positive terminals and dendrites and a few substance P-positive fine fibres possessing varicosities also were observed in the ND. Following WGA-HRP injection in the ND, dense terminal labelling was seen ipsilaterally in the rostral half of the medial accessory olive, suggesting that there may be a certain degree of mediolateral and dorsoventral topographic correspondance within the ND-olive projection. In the same cases, many cell bodies containing HRP reaction product also were found 1) ipsilaterally in the motor cortex, anterior pretectal nucleus, and a restricted area of the caudal part of the substantia nigra pars reticulata; 2) contralaterally in the anterior and posterior interposed cerebellar nuclei as well as in a portion of the lateral cerebellar nucleus; and 3) bilaterally in the zona incerta, the posterior pretectal nucleus, the pedunculopontine tegmental nuclei, the spinal trigeminal nucleus, the dorsal column nuclei, and the spinal cord. Details of the interrelationships and functional considerations amongst the ND, adjacent nuclei, and longitudinal zones of the cerebellum are discussed.

Metabotropic glutamate receptors and visual cortical synaptic plasticity.

Two forms of use-dependent synaptic plasticity, called long-term potentiation (LTP) and long-term depression (LTD), can be elicited in the visual cortex following different paradigms of electrophysiological stimulation. These neurobiological phenomena often are considered as necessary components of models for the alteration in function of the nervous system that must occur at some level for the establishment and (or) maintenance of memory engrams, for learning processes, or for the consolidation of active neural connections and regression of inactive contacts in the developing brain. It has been postulated that for LTP and LTD to be produced in the hippocampus, activation of a particular subtype of excitatory amino acid receptor, the metabotropic receptor, is a critical requirement. Only recently has it become possible to test this hypothesis directly, as a new compound, (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG), has been introduced and the suggestion made that it selectively antagonizes the metabotropic receptor. This substance has been tested in the present study on responses recorded from slices of rat visual cortex and has been found both to block the activation of the metabotropic receptor and to interfere selectively with the form of synaptic plasticity called LTD. It thus appears from the experiments reported in this paper as though the metabotropic receptor subtype that is blocked by MCPG is required for the expression of LTD but not for the expression of LTP, in the visual cortex of adult rats.

Induction of LTD but not LTP through metabotropic glutamate receptors in visual cortex.

Long-term potentiation (LTP) and long-term depression (LTD), often used as essential components in synaptic models for learning, memory and forgetting, can be produced in cortical tissue by repetitive activation of neural pathways under different stimulus conditions. The involvement of metabotropic glutamate receptors (mGluRs) has been postulated to be necessary for the establishment of either or both forms of synaptic plasticity in hippocampus. The recent introduction of a specific antagonist for mGluRs, (+/-)-alpha-methyl-4-carboxyphenylglycine, prompted the investigation of the respective involvement of this receptor population in the induction of LTP and LTD in visual cortex of the rat in vitro. The results suggest the critical involvement of mGluRs in producing LTD but not LTP.

Thromboxane and pulmonary morphometry in the development of the pulmonary hypertensive response to group B streptococcus.

OBJECTIVE: To clarify the mechanism of the development of a severe pulmonary hypertensive response to group B streptococcus. DESIGN: Prospective, randomized controlled trial. SUBJECTS: Twelve chronically instrumented and six age-matched uninstrumented newborn piglets. INTERVENTIONS: Six animals received eight injections of group B streptococcus over an 11-day period (control group). Six additional animals (pretreatment group) were given 3 mg/kg of dazmegrel, a thromboxane synthase blocking agent, before each dose of group B streptococcus to prevent the pulmonary hypertensive response and to control for any secondary arterial remodeling. MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements, pulmonary arterial morphometry, and thromboxane concentrations were examined in the instrumented animals. Lungs from the uninstrumented piglets were examined to determine morphometric norms for this population. The animals given only group B streptococcus developed a significant pulmonary hypertensive response after five daily doses (+6.8 +/- 2.0 [SEM] mm Hg, p < .05) which became pronounced after eight doses (+13.2 +/- 1.0 mm Hg). Pulmonary hypertension was not observed in the pretreatment group when dazmegrel was given; however, on the final day in this group, dazmegrel was withheld before group B streptococcus dosing and a significant pulmonary hypertensive response was observed (+20 +/- 1.6 mm Hg). The medial thickness of pulmonary arteries was not different between the two groups nor when compared with that of six normal, uninstrumented animals. Plasma thromboxane B2 concentrations were determined from blood samples taken before and after group B streptococcus infusion at the first, seventh and eighth (final) dosing. Thromboxane concentrations increased significantly on days 7 and 8 in the control group (578 +/- 312 to 752 +/- 372 pg/mL, 638 +/- 201 to 1462 +/- 295 pg/mL, respectively) and on day 8 in the pretreatment group (545 +/- 160 to 705 +/- 187 pg/mL). CONCLUSIONS: We conclude that the development of potentiated pulmonary hypertension is not due to pulmonary arterial remodeling, but is associated with increased thromboxane production.

Amino acids modify thalamo-cortical response transformation expressed by neurons of the ventrobasal complex.

The hypothesis has been tested that inhibitory mechanisms, active spatially and temporally between the input and the output of thalamic neurons, determine the nature of the information transmitted to the cerebral cortex. To enable this assessment, in barbiturate-anesthetized cats and urethane-anesthetized rats juxtacellular recordings were performed together with microiontophoretic ejection of transmitter agonists and antagonists. The effects of these drugs were studied on responses evoked by mechanical stimulation of cutaneous receptive fields (RFs) of neurons in the thalamic ventrobasal complex (VB). Neurons from different parts of the VB were investigated: 29 units were located medially, in the ventral posteromedial nucleus (VPM; facial RFs), and 11 units were located laterally, in the ventral posterolateral nucleus (VPL; forepaw and body RFs). A further eleven VB units had no detectable RF. Twenty-six neurons were tested with electrical stimulation of the somatosensory cortex (SI), 17 of these being identified as thalamo-cortical relay neurons and 5 being classified as presumed interneurons; the remaining 4 could not be activated. Four additional recordings were from trigemino-thalamic or thalamo-cortical fibers. For the quantitative assessment of the neurons' input and output, neuronal activity was induced by feedback-controlled, mechanical trapezoidal and/or sinusoidal stimuli applied to sinus hairs, fur or skin and the numbers of prepotentials and soma spikes were compared in peristimulus time histograms (PSTHs) generated simultaneously for both types of signal from 'DC' recordings. Iontophoretic administration of excitatory amino acids (EAAs) or bicuculline methiodide (BMI) increased output-input ratios in 87% of the cases tested, due to a higher rate of conversion of prepotentials into soma spikes taking place. In cases of neurons exhibiting a sustained-to-transient response pattern, changes to sustained-to-sustained patterns were demonstrated. Tests with gamma-aminobutyric acid (GABA) produced decreased output-input ratios in 90% of the neurons, due to a lower conversion rate of prepotentials into soma spikes taking place. In cases of neurons exhibiting high output-input ratios (sustained-to-sustained type), the responses changed to the sustained-to-transient pattern. For cortically evoked antidromic spikes of VB neurons, GABA produced a failure of the initial segment (IS-) spike to invade the soma, whereas BMI and glutamate (Glu) facilitated soma depolarization. When ejected with relatively higher currents than those needed to alter output-input ratios, EAAs decreased prepotential amplitudes while GABA produced increases in 16 of 18 neurons.(ABSTRACT TRUNCATED AT 400 WORDS)