Biomedical subjects

E G Jones

Publications and source records attributed to E G Jones.

At least 73 records · Page 4Linked to original sources

PubMed1997

Differential and time-dependent changes in gene expression for type II calcium/calmodulin-dependent protein kinase, 67 kDa glutamic acid decarboxylase, and glutamate receptor subunits in tetanus toxin-induced focal epilepsy.

To study potential molecular mechanisms of epileptogenesis in the neocortex, the motor cortex of rats was injected with tetanus toxin (TT), and gene expression for 67 kDa glutamic acid decarboxylase (GAD-67), type II calcium/calmodulin-dependent protein kinase (CaMKII), NMDA receptor subunit 1 (NR1), and AMPA receptor subunit 2 (GluR2) was investigated by in situ hybridization histochemistry. Injections of 20-35 ng TT induced recurrent seizures after a postoperative period ranging from 4 to 13 d. A majority of rats perfused 5-7 d after TT injection showed altered gene expression, but the changes varied in their areal extent, ranging from most neocortical areas on the injected side in some rats to mainly the frontoparietal cortex or the motor cortex in others. Epileptic rats perfused 14 d after TT injection showed a focus of increased GAD-67 and NR1, and of decreased alpha-CaMKII and GluR2 mRNA levels at the injection site. A zone of cortex surrounding the focus showed changes in alpha-CaMKII, GAD-67, and NR1 mRNA levels that were reciprocal to those in the focus. The results suggest that TT-induced seizure activity initially spread to a variable extent but was gradually restricted 2-3 d after seizure onset. The focus and the surround showing reciprocal changes in gene expression are thought to correspond to the electrophysiologically identified epileptic focus and inhibitory surround, respectively. The findings suggest that lateral inhibition between neighboring cortical regions will be affected and contribute to a neurochemical segregation of an epileptic focus from surrounding cortex.

Animals↗

PubMed1997

Workshop on schizophrenia.

On November 29-30, 1995, the National Academy of Sciences and the Institute of Medicine brought together experts in schizophrenia and specialists in other areas of the biological sciences in a workshop aimed at promoting the application of the latest biological information to this clinical problem. The workshop paid particular attention to evidence of pathology in the brains of people with schizophrenia, and to the possibility that this reflects an abnormality in brain development that eventually leads to the appearance of symptoms. The participants were impressed with the complexity of the problem, and felt that multiple approaches would be required to understand this disease. They recommended that a major focus should be on the search for predisposing genes, but that there should be parallel research in many other areas.

Brain↗

PubMed1997

Maturation of neuronal form and function in a mouse thalamo-cortical circuit.

Postnatal development of physiological properties underlying slow intrathalamic oscillations was studied by whole-cell recording from synaptically coupled neurons of the reticular nucleus (RTN) and ventral posterior nucleus (VPN) of mouse brain slices in vitro and compared with the morphological development of dye-injected cells. Between postnatal days 3 and 11 (P3-P11), progressive changes in RTN and VPN neurons included shortening of the membrane time constant, decreasing input resistance, and lowering of the resting membrane potential (RMP). Low-threshold Ca2+ spikes (LTS) were present from P3, but their capacity to sustain multispike bursts was limited before P11. Synaptic responses were evoked in RTN and VPN neurons by electrical stimulation of the internal capsule from P3. Younger RTN neurons responded with a single spike, but their capacity to fire bursts gradually improved as the RMP reached levels below the LTS activation potential. Concomitantly, as the reversal potential of the inhibitory postsynaptic potential in VPN neurons became more negative, its capacity to deinactivate the LTS increased, and rebound bursts that could maintain oscillations were produced; sustained oscillations became the typical response to internal capsule stimulation at P12. The functional maturation of the intrathalamic circuitry, particularly between P10 and P14, occurs in parallel with the morphological maturation (size, dendritic growth, and dendritic field structure) of individual RTN and VPN neurons, as studied by confocal microscopy. Maturation of RTN cells led that of VPN cells by 2-3 d. The appearance of intrathalamic oscillations is probably correlated with the appearance of slow-wave sleep in postnatal animals.

Aging↗

PubMed1997

Cortical development and thalamic pathology in schizophrenia.

In this article, morphological data suggesting that brain development may be altered in schizophrenia are reviewed in relation to the major events in neural development. In the absence of severe defects in brain structure in individuals with schizophrenia, developmental processes governing the establishment, refinement, and maintenance of connections are potential sites of pathological involvement. Alterations in connectional patterns are likely to result in activity-dependent changes in gene expression for molecules involved in the neurotransmission process, with functional consequences. Loss of cells in the thalamus may be primary or secondary to cortical or other subcortical pathology. Loss of thalamic cells and/or of corticothalamic inputs could lead to disintegration of thought processes by a failure in functional brain states dependent on collective oscillation of large ensembles of cortical and thalamic neurons.

Cerebral Cortex↗

PubMed1997

Localization of CAM II kinase-alpha, GAD, GluR2 and GABA(A) receptor subunit mRNAs in the human entorhinal cortex.

The human entorhinal cortex (ERC) is an important relay between neocortical association areas and the hippocampus. Pathology in this area, including disturbances in its unique cytoarchitecture and alterations in neurotransmitter receptor binding, has been implicated in several neuropsychiatric disorders but details of the patterns of gene expression for molecules involved in the major neurotransmitter systems in this cortex have been lacking. We used in situ hybridization histochemistry to localize the mRNAs for several proteins which are involved in excitatory and inhibitory neurotransmission in the human ERC. Labelling of mRNA for a glutamate receptor subunit (GluR2) and for a marker of glutamatergic cortical neurons (alpha type II calcium/calmodulin-dependent protein kinase) were distributed in a laminar manner which matched the cellular packing seen on the Nissl sections, with particularly high levels of labelling in the layer II (pre-alpha) cell clusters characteristic of this cortex. Cells labelled for the mRNA of 67 kDa glutamic acid decarboxylase, the synthesizing enzyme of GABA, were distributed diffusely throughout all layers, not concentrated in the cell clusters, and were present in higher numbers in layer III. The labelling of mRNAs for the alpha1, beta2 and gamma2 subunits of the GABA(A) receptor, however, was distributed in a laminar pattern similar to that for GluR2 and CAM II kinase mRNAs, implying a high concentration of inhibitory synapses on the excitatory cells which express these mRNAs.

Adult↗

PubMed1997

GABA(B)-receptor-mediated inhibition in developing mouse ventral posterior thalamic nucleus.

Inhibitory postsynaptic potentials (IPSPs) generated by activation of the thalamic reticular nucleus (RTN) were recorded in neurons of the ventral posterior nucleus (VP) in vitro in slices from mice aged postnatal day (P)1-P17. An early IPSP peaking 41 +/- 2.5 (SE) ms after electrical stimulation of the internal capsule or RTN was found in 96% of VP neurons. This early IPSP was blocked by bicuculline, showing its dependence on gamma-aminobutyric acid-A (GABA(A)) receptors. A late IPSP peaking 357 +/- 27 ms after the stimulus was observed in 22% of VP neurons in control medium but was uncovered in 38% of neurons when bicuculline was added. The late IPSP was blocked by addition of a GABA(B) antagonist, 2-hydroxysaclofen, to the medium (n = 7); it had a reversal potential of -98 +/- 1.3 mV, 14 mV negative to the early component. In contrast to the early IPSP, whose reversal potential became more negative during postnatal development, the reversal potential of the late IPSP remained constant throughout the postnatal period studied. The most significant change in the late IPSP was shortening in duration, with reduction in latency-to-peak by >400 ms, between P1 and P10. No changes of comparable magnitude were observed in the duration of the earlier GABA(A) response. These results show that both GABA(A) and GABA(B) IPSPs are present very early in the postnatal thalamus and that their characteristics evolve along independent paths during postnatal development.

Animals↗

PubMed1997

Toward an agreement on terminology of nuclear and subnuclear divisions of the motor thalamus.

The nomenclature most commonly applied to the motor-related nuclei of the human thalamus differs substantially from that applied to the thalamus of other primates, from which most knowledge of input-output connections is derived. Knowledge of these connections in the human is a prerequisite for stereotactic neurosurgical approaches designed to alleviate movement disorders by the placement of lesions in specific nuclei. Transfer to humans of connectional information derived from experimental studies in nonhuman primates requires agreement about the equivalence of nuclei in the different species, and dialogue between experimentalists and neurosurgeons would be facilitated by the use of a common nomenclature. In this review, the authors compare the different nomenclatures and review the cyto- and chemoarchitecture of the nuclei in the anterolateral aspect of the ventral nuclear mass in humans and monkeys, suggest which nuclei are equivalent, and propose a common terminology. On this basis, it is possible to identify the nuclei of the human motor thalamus that transfer information from the substantia nigra, globus pallidus, cerebellum, and proprioceptive components of the medial lemniscus to prefrontal, premotor, motor, and somatosensory areas of the cerebral cortex. It also becomes possible to suggest the principal functional systems involved in stereotactically guided thalamotomies and the functional basis of the symptoms observed following ischemic lesions in different parts of the human thalamus.

Afferent Pathways↗

PubMed1997

Toward an agreement on terminology of nuclear and subnuclear divisions of the motor thalamus.

Afferent Pathways↗

PubMed1997

Area and lamina-specific expression of GABAA receptor subunit mRNAs in monkey cerebral cortex.

Seven monkey-specific cDNAs corresponding to alpha 1, alpha 2, alpha 4, alpha 5, beta 1, beta 2, and gamma 2 GABAA receptor subunits were isolated and cloned; radioactive cDNA and cRNA probes were used for Northern blot analysis and in situ hybridization histochemistry of the primary visual, somatosensory, motor, temporal, and anterior parietal areas. alpha 1, beta 2, and gamma 2 subunit mRNAs were expressed at much higher levels than the other mRNAs, indicating that most cortical GABAA receptors are assembled from these three subunits. alpha 1, beta 2, and gamma 2 were also more highly expressed in area 17 than in all other areas, reflecting the greater density of GABA cells and synapses in area 17. In all cortical areas, each subunit mRNA showed an individual pattern of laminar expression. alpha 1, beta 2, and gamma 2 subunit mRNAs were particularly high in layers II-III, IV, and VI, tending to follow patterns of receptor binding and immunocytochemical staining. The other transcripts had different patterns, which did not match binding or immunocytochemical localization patterns. alpha 5 subunit mRNAs, which are highly expressed in development, were enriched in layer VI and the underlying white matter of visual cortex and in a layer IV-like strip in area 4, possibly reflecting the involvement of receptors formed from alpha 5 polypeptides in trophic interactions in the cortical subplate and in the transient layer IV during development of these areas. Monocular deprivation for 1-3 weeks, induced by intravitreal injection of tetrodotoxin, resulted in substantial reductions in levels of alpha 1, beta 2, and gamma 2 subunit mRNAs in deprived ocular dominance columns of the visual cortex, but the other subunit mRNAs were largely unaffected by monocular deprivation. In cortical layers in which expression of any of the transcripts was high, all neurons appeared to express the gene, but in layers in which expression was low or moderate, differences in the degree of labeling of individual neurons suggested that some neurons may not express certain subunit transcripts in detectable amounts. Laminar differences in expression of different GABAA receptor subunits in cerebral cortex suggest the assembly of functional receptors from different arrangements of available subunits in different types of cell. Receptors with different functional properties may be assembled from different combinations of subunit polypeptides in different layers and in the visual cortex may be differentially regulated under activity-dependent conditions.

Animals↗

PubMed1996

Decrease in sigma but no increase in striatal dopamine D4 sites in schizophrenic brains.

[3H]Nemonapride differentially defines sigma and dopamine receptor sites depending upon assay conditions. In post-mortem schizophrenic brain tissues, [3H]nemonapride-labeled sigma receptor binding is decreased compared to match normal controls. No striatal dopamine D4/D4-like receptor differential was observed between the schizophrenic or control tissues, using the [3H]nemonapride minus [3H]raclopride subtraction method.

Adult↗

PubMed1996

Developmental and stimulus-specific expression of the immediate-early gene zif268 in rat spinal cord.

Expression of the cellular immediate-early gene, zif268, was investigated using immunocytochemical methods in cervical spinal cord of neonatal and adult rats. The postnatal expression of zif268 follows a specific temporal and spatial sequence in the spinal dorsal horn. Neurons immunoreactive for Zif268 protein were not present in cervical spinal cord before postnatal day (P) 6. At P6 they were occasionally observed in Rexed's lamina 1. By P11, a few additional, faintly labeled, Zif268-positive neurons appeared in lamina III Around P16, however, many immunoreactive neurons were found in laminae I-III and a few in laminae IV-VII. The number of Zif268-immunoreactive neurons decreased markedly by P21 and was further reduced by P26 to become virtually absent in adult rats. In adults, surgical exposure of peripheral nerves alone enhanced Zif268 expression, but this effect largely disappeared in less than 6 h. Electrical stimulation of the nerves with high-frequency long trains, typical of those known to elicit long-term neural plasticity, induced a marked increase in Zif268 expression in the dorsal horn. Stimulation with single pulses had a much weaker effect, Zif268 may thus play a role in stimulus-induced, long-term neural plasticity in the spinal cord.

Animals↗

PubMed1996

Representation of face and intra-oral structures in area 3b of macaque monkey somatosensory cortex.

Details of the representation of body regions innervated by the trigeminal nerve were elucidated in monkey cerebral cortex. Microelectrode recording was used to generate somatosensory maps in the posterior bank of the central sulcus and on the exposed cortical surface lateral to the lateral tip of the central sulcus in Macaca nemestrina. The area innervated by the contralateral trigeminal nerve is represented in an 8-mm mediolateral extent of area 3b lateral to the representation of the hand. Lateral to this, still within area 3b, there is an expanded representation of ipsilateral intra-oral structures measuring 6 mm in mediolateral extent. Both representations fill area 3b anteroposteriorly. The ipsilateral representation forms approximately 40% of the trigeminal representation, consistent with the amount of the ventroposterior medial (VPM) thalamic nucleus devoted to representation of ipsilateral intra-oral structures. Comparison of the present results with maps of the face representation in other species of monkey shows a consistent somatotopy of the face between species; size variations are mainly related to the enlarged ipsi- and contralateral representations of the cheek pouches in macaques. The general somatotopy of the trigeminal representation in monkeys is consistent with that in other mammalian species.

Animals↗

PubMed1996

Plasticity of the somatosensory cortical map in macaque monkeys after chronic partial amputation of a digit.

Activity-dependent changes in cortical representational maps have been reported in many studies of adult mammals. Limits in extent of change have been attributed to limited divergence in the thalamocortical projection. However, studies have commonly been restricted to animals surviving less than a year following relatively modest peripheral sensory perturbations. After extensive deafferentation and long-term survival, more extensive changes, seemingly beyond the limits of thalamocortical divergence, have been reported. We report changes in the somatotopic map in area 3b of an adult macaque monkey, in which part of the index finger of one hand had been amputated two years previously. The representation of the remaining stump occupied the whole region of area 3b normally devoted to the representation of the entire digit. The skin surrounding the stump appeared to have been hyperinnervated by axons severed during the amputation. The hyperinnervation of remaining skin may have reactivated neurons of the somatosensory system silenced by the amputation, leading to the recovery of a cortical map but with a modified organization.

Amputation, Surgical↗

PubMed1996

Localization of alpha type II calcium calmodulin-dependent protein kinase at glutamatergic but not gamma-aminobutyric acid (GABAergic) synapses in thalamus and cerebral cortex.

The alpha subunit of type II calcium/calmodulin-dependent protein kinase (CAM II kinase-alpha) plays an important role in longterm synaptic plasticity. We applied preembedding immunocytochemistry (for CAM II kinase-alpha) and postembedding immunogold labeling [for glutamate or gamma-aminobutyric acid (GABA)] to explore the subcellular relationships between transmitter-defined axon terminals and the kinase at excitatory and inhibitory synapses in thalamus and cerebral cortex. Many (but not all) axon terminals ending in asymmetric synapses contained presynaptic CAM II kinase-alpha immunoreactivity; GABAergic terminals ending in symmetric synapses did not. Postsynaptically, CAM II kinase-alpha immunoreactivity was associated with postsynaptic densities of many (but not all) glutamatergic axon terminals ending on excitatory neurons. CAM II kinase-alpha immunoreactivity was absent at postsynaptic densities of all GABAergic synapses. The findings show that CAM II kinase-alpha is selectively expressed in subpopulations of excitatory neurons and, to our knowledge, demonstrate for the first time that it is only associated with glutamatergic terminals pre- and postsynaptically. CAM II kinase-alpha is unlikely to play a role in plasticity at GABAergic synapses.

Animals↗

PubMed1996

Nucleus-specific expression of GABA(A) receptor subunit mRNAs in monkey thalamus.

Expression of 10 GABAA receptor subunit genes was examined in monkey thalamus by in situ hybridization using cRNA probes specific for alpha 1, alpha 2, alpha 3, alpha 4, alpha 5, beta 1, beta 2, beta 3, gamma 1, and gamma 2 subunit mRNAs. These displayed unique hybridization on patterns with significant differences from rodents. Alpha 1, beta 2, and gamma 2 transcripts were expressed at high levels in all dorsal thalamic nuclei, but expression was significantly higher in sensory relay nuclei-especially the dorsal lateral geniculate nucleus. Other transcripts showed nucleus-specific differences in levels of expression and in the range expressed. Alpha 5 and alpha 4 subunit transcripts were expressed in all nuclei except the intralaminar nuclei. Levels of alpha 2, alpha 3, beta 1, beta 3, and gamma 1 expression were very low, except in intralaminar nuclei. In the reticular nucleus, most subunit transcripts were not expressed, and only gamma 2 transcripts were consistently detected at modest levels. Thalamic GABAA receptors may be assembled from nucleus-specific groupings of subunit polypeptides.

Animals↗

PubMed1996

Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients.

BACKGROUND: The cortical subplate is a transitory structure involved in the formation of connections in developing cerebral cortex. Interstitial neurons, normally present in subcortical white matter (WM) of the adult brain, have escaped the programmed cell death that eliminates most subplate neurons. Previous investigations indicated a maldistribution of one population of interstitial neurons in the WM of brains of schizophrenic patients, suggesting a defect of the subplate during brain development. METHODS: Three histochemically or immunocytochemically defined neuronal populations were studied in WM beneath the middle frontal gyrus of 20 schizophrenic patients and 20 matched control subjects. RESULTS: Brains of schizophrenic patients showed significant changes in the distribution of the three neuronal populations: microtubule-associated protein 2 and nonphosphorylated neurofilament-immunoreactive neurons showed a decreased density in superficial WM and an increased density in deeper WM. Nicotinamide adenine dinucleotide phosphate-diaphorase neurons were reduced in superficial WM and showed variable densities in deeper WM. Thirty-five percent of the brains of schizophrenic patients but no brains of the control subjects showed a maldistribution of neurons toward deeper WM with at least two of the three markers. Changes in neuronal distribution were not linked to age, gender, autolysis time, or subtype of schizophrenia. CONCLUSIONS: Selective displacement of interstitial WM neurons in the frontal lobe of brains of schizophrenic patients may indicate alteration in the migration of subplate neurons or in the pattern of programmed cell death. Both could lead to defective cortical circuitry in the brains of schizophrenic patients.

Adult↗

PubMed1996

Stimulus-dependent, reciprocal up- and downregulation of glutamic acid decarboxylase and Ca2+/calmodulin-dependent protein kinase II gene expression in rat cerebral cortex.

Long-train tetanic stimulation of the cerebral cortex induces long-term changes in the excitability of cortical neurons, while short-train electrical stimulation does not. In the present study, we show that both forms of stimulation when applied to rat motor cortex for 4 h enhance c-fos expression, but only tetanic stimulation, when imposed upon short-train stimulation, modulates gene expression for 67-kDa glutamic acid decarboxylase (GAD) and alpha Ca2+/calmodulin-dependent protein kinase II (CaMKII alpha). Gene expression for beta Ca2+/calmodulin-dependent protein kinase II is not affected by either stimulation mode. GAD messenger RNA (mRNA) is increased from 1 h after the end of tetanization to the longest poststimulus survival time investigated (14 h). CaMKII alpha mRNA is decreased 1-3 h after the end of tetanization but thereafter returns to prestimulus levels. These results imply not only that mechanisms underlying neocortical plasticity are stimulus-dependent but also that they involve reciprocal changes in molecules regulating the balance of excitation and inhibition.

Animals↗

PubMed1996

Peripheral nerve stimulation increases Fos immunoreactivity without affecting type II Ca2+/calmodulin-dependent protein kinase, glutamic acid decarboxylase, or GABAA receptor gene expression in cat spinal cord.

Expression patterns of the immediate early gene c-fos and of other genes including those for the alpha-subunit of type II Ca2+/calmodulin-dependent protein kinase (CaMKII alpha), 67-kDa glutamic acid decarboxylase (GAD), and the alpha 1-, beta 2-, and gamma 2-subunits of the GABAA receptor were described in the spinal cord of normal cats and following peripheral nerve stimulation. As revealed by in situ hybridization histochemistry, CaMKII alpha messenger RNA (mRNA) is normally distributed only in cells of Rexed's laminae I-IV, whereas GAD mRNA is expressed by subpopulations of cells in all laminae, with the heaviest hybridization signal found in laminae I-III and medial parts of laminae V and VI. The three GABAA receptor subunits have varying expression patterns in the laminae. All of them are expressed by many cells located in the base of the dorsal horn and the intermediate zone, but only the gamma 2-subunit is intensely expressed by motoneurons. Single-pulse, electrical stimulation of the sciatic or median and ulnar nerve of anesthetized cats at a pulse rate of 1/s for 6-8 h failed to induce observable changes in gene expression for CaMKII alpha, GAD, or for the three subunits of the GABAA receptor; although immunoreactivity for the protein products of c-fos (or c-fos-related genes) was markedly upregulated in some neurons of the dorsal horn and the intermediate zone. Therefore, under the present experimental conditions, upregulation of the immediate early gene c-fos (or c-fos-related genes) is not associated with changes in expression of late-effector genes potentially involved in central nervous system plasticity.

Animals↗