Perinatal anoxia degrades auditory system function in rats.

Little is known about the neural bases of the reduced auditory and cortical processing speeds that have been recorded in language-impaired, autistic, schizophrenic, and other disabled human populations. Although there is strong evidence for genetic contributions to etiologies, epigenetic factors such as perinatal anoxia (PA) have been argued to be contributors, or causal, in a significant proportion of cases. In this article, we explored the consequences of PA on this elementary aspect of auditory behavior and on auditory system function in rats that were briefly perinatally anoxic. PA rats had increased acoustic thresholds and reduced processing efficiencies recorded in an auditory behavioral task. These rats had modestly increased interpeak intervals in their auditory brainstem responses, and substantially longer latencies in poststimulus time histogram responses recorded in the primary auditory cortex. The latter were associated with degraded primary auditory cortex receptive fields and a disrupted tonotopy. These processing deficits are consistent with the parallel behavioral and physiological deficits recorded in children and adults with a history of language-learning impairment and autism.

Effects of sensorimotor restriction and anoxia on gait and motor cortex organization: implications for a rodent model of cerebral palsy.

Chronic or acute perinatal asphyxia (PA) has been correlated with the subsequent development of cerebral palsy (CP), a developmental neurological disorder characterized by spasticity and motor abnormalities often associated with cognitive deficits. Despite the prevalence of CP, an animal model that mimics the lifetime hypertonic motor deficits is still not available. In the present study, the consequences of PA on motor behavior, gait and organization of the primary motor cortex were examined in rats, and compared with the behavioral and neurological consequences of early postnatal movement-restriction with or without oxygen deprivation. Rats subjected to PA had mild increases in muscular tone accompanied by subtle differences in walking patterns, paralleled by significantly altered but relatively modest disorganization of their primary motor cortices. Movement-restricted rats, suffering PA or not, had reduced body growth rate, markedly increased muscular tone at rest and with active flexion and extension around movement-restricted joints that resulted in abnormal walking patterns and in a profoundly distorted representation of the hind limbs in the primary motor cortex. Within the sensorimotor-restricted groups, non-anoxic rats presented the most abnormal pattern and the greatest cortical representational degradation. This outcome further supports the argument that PA per se may represent a substrate for subtle altered motor behaviors, and that PA alone is sufficient to alter the organization of the primary motor cortex. At the same time, they also show that early experience-dependent movements play a crucial role in shaping normal behavioral motor abilities, and can make a powerful contribution to the genesis of aberrant movement abilities.

The chemo- and somatotopic architecture of the Galago cuneate and gracile nuclei.

The pattern of peripheral nerve inputs into the dorsal column nuclei, cuneate and gracile, was investigated in the prosimian Galago garnetti. The major findings were, that there is a greater segregation of the inputs from the fingers/hand within the cuneate compared with input form the toes/foot within the gracile. In both nuclei, cell clusters can be identified as cytochrome oxidase dense blotches, reactive also for the activity-dependent enzyme nitric oxide synthase. In the cuneate, cell clusters were apparent as six main cytochrome oxidase/nitric oxide synthase-reactive ovals arranged in a medial to lateral sequence. In contrast in the gracile, a higher degree of parcellation was noted and several cytochrome oxidase/nitric oxide synthase blotches were distributed along the rostrocaudal axis of the nucleus. This different architecture parallels differences in the organization of the inputs from the hand and from the foot. In the cuneate, cholera toxin B subunit conjugated to horseradish peroxydase labeled terminals from the glabrous and hairy skin of digits d1 to d5 segregated in each of the five most lateral cytochrome oxidase/nitric oxide synthase blotches. Afferents from the thenar, palmar pads and hypothenar overlapped with those from digit 1, digit 2 to digit 4 and digit 5, respectively. Inputs from wrist arm and shoulder were segregated in the most medial blotch. In the gracile, multiple foci of cholera toxin B subunit conjugated to horseradish peroxydase labeled terminals were observed upon injections of single sites in the toes or plantar pads. Although in multiple foci, inputs from different toes segregated from one another as well. Terminals from the plantar pads appeared to converge on the same cytochrome oxidase/nitric oxide synthase blotches targeted by inputs from the toes. In both the cuneate and the gracile, cytochrome oxidase/nitric oxide synthase blotches also presented intense immunoreactivity for GABA, calbindin, parvalbumin, and brain derived neurotrophic factor. Finally, in the cuneate the cell cluster region presented similarities in prosimian galagos and four species of New World monkeys, whereas it appeared more differentiated and complex in the Old Word macaque monkeys. In conclusion, the different pattern of segregation of the inputs from the hand and from the foot can be related to the different metabolic organization of the cuneate and of the gracile, respectively.

[Primary gastric lymphoma: a case report]. / Linfoma gastrico primitivo: descrizione di un caso clinico.

In this case report the Authors describe a case of primary gastric lymphoma in a 62 years old patient who presented with dyspepsia and weigh loss. Primary gastric lymphoma is a rare neoplasm which of 1-10% of the malignant gastric neoplasms in the gastroenteric tract. The clinic presentation is usually aspecific. The infection by H. pylori is a factor of predisposition for this kind of disease. The diagnostic pathway consists in x-ray examination of the gastrointestinal tract, the endoscopy with biopsies, the computerized tomography and the echo-endoscopy. However obtaining a preoperative diagnosis is often difficult because of the submucosal localization of the lymphoma. There is not a common strategy among the Authors for the treatment of the disease, which can be surgical, radiotherapic or chemotherapic.

Sensory enrichment after peripheral nerve injury restores cortical, not thalamic, receptive field organization.

Sensory perception can be severely degraded after peripheral injuries that disrupt the functional organization of the sensory maps in somatosensory cortex, even after nerve regeneration has occurred. Rehabilitation involving sensory retraining can improve perceptual function, presumably through plasticity mechanisms in the somatosensory processing network. However, virtually nothing is known about the effects of rehabilitation strategies on brain organization, or where the effects are mediated. In this study, five macaque monkeys received months of enriched sensory experience after median nerve cut and repair early in life. Subsequently, the sensory representation of the hand in primary somatosensory cortex was mapped using multiunit microelectrodes. Additionally, the primary somatosensory relay in the thalamus, the ventroposterior nucleus, was studied to determine whether the effects of the enrichment were initiated subcortically or cortically. Age-matched controls included six monkeys with no sensory manipulation after median nerve cut and regeneration, and one monkey that had restricted sensory experience after the injury. The most substantial effect of the sensory environment was on receptive field sizes in cortical area 3b. Significantly greater proportions of cortical receptive fields in the enriched monkeys were small and well localized compared to the controls, which showed higher proportions of abnormally large or disorganized fields. The refinements in receptive field size and extent in somatosensory cortex likely provide better resolution in the sensory map and may explain the improved functional outcomes after rehabilitation in humans.

Thalamic and cortical contributions to neural plasticity after limb amputation.

Little is known about the substrates for the large-scale shifts in the cortical representation produced by limb amputation. Subcortical changes likely contribute to the cortical remodeling, yet there is little data regarding the extent and pattern of reorganization in thalamus after such a massive deafferentation. Moreover, the relationship between changes in thalamus and in cortex after injuries of this nature is virtually unexplored. Multiunit microelectrode maps were made in the somatosensory thalamus and cortex of two monkeys that had long-standing, accidental forelimb amputations. In the deprived portion of the ventroposterior nucleus of the thalamus (VP), where stimulation to the hand would normally activate neurons, new receptive fields had emerged. At some recording sites within the deprived zone of VP, neurons responded to stimulation of the remaining stump of the arm and at other sites neurons responded to stimulation of both the stump and the face. This same overall pattern of reorganization was present in the deprived hand representation of cortical area 3b. Thus thalamic changes produced by limb amputation appear to be an important substrate of cortical reorganization. However, a decrease in the frequency of abnormal stump/face fields in area 3b compared with VP and a reduction in the size of the fields suggests that cortical mechanisms of plasticity may refine the information relayed from thalamus.

GABA excites immature CA3 pyramidal cells through bicuculline-sensitive and -insensitive chloride-dependent receptors.

Intracellular and patch clamp recording techniques were used to investigate the role of GABA in immature CA3 hippocampal neurons. During the first postnatal week spontaneous GABA release was detected as spontaneous ongoing synaptic potentials (SPSPs) or giant depolarizing potentials (GDPs). GDPs were generated at regular intervals and regulated by ionotropic glutamate receptors (GluRs), whereas SPSPs occurred randomly and were unaffected by ionotropic GluRs. Both GDPs and SPSPs were positively modulated by metabotropic GluRs through cyclic AMP-dependent protein kinase. Moreover GABA controlled its own release through GABAA and GABAB receptors, probably localized on GABAergic nerve terminals. At this developmental stage, GABA depolarized CA3 pyramidal cells through two distinct classes of chloride-permeable receptors: bicuculline sensitive and insensitive, respectively. The bicuculline-insensitive responses were blocked by picrotoxin in a noncompetitive way. Whole-cell GABA currents, recorded in the presence of bicuculline, had a slower desensitization rate and faster recovery from desensitization. In excised outside-out patches, in the presence of bicuculline, GABA activated single-channel currents with conductances of 14, 22, and 31 pS. These values were similar to those obtained when GABA was applied in the absence of bicuculline. Interestingly, GABA responses obtained in the absence of bicuculline, were sensitive to the blocking effect of zinc, whereas bicuculline-resistant responses were almost unaffected by this divalent cation. Expression of different subunits in native receptors (particularly of the alpha and rho type) may account for the functional differences observed in the present experiments. Activation of bicuculline-insensitive receptors would strengthen and prolong the depolarizing action of GABA, thus favoring the entry of calcium through voltage-dependent calcium channels. This calcium signal may be essential in promoting stabilization of synaptic contacts during a critical period of postnatal development.

Nitric oxide sensitive depolarization-induced hyperpolarization: a possible role for gap junctions during development.

Electrical coupling is a widespread feature of developing neuronal circuits and it contributes to the generation of patterned activity. In the developing rat hippocampus, release of GABA by coactive hilar interneurones generates widespread synchronized activity. Here it is shown that hilar interneurones strongly rectify in the outward direction when depolarized. This depolarization-induced hyperpolarization, abolished by gap junction uncouplers, is modulated by nitric oxide. This phenomenon might represent a current-shunting mechanism of the excess current by providing functional inhibition at a developmental stage when GABA is excitatory. Spatial buffering of the current might represent an osmotic mechanism for growth and differentiation.

Intrinsic oscillations in CA3 hippocampal pyramids: physiological relevance to theta rhythm generation.

The theta rhythm is the most remarkable hippocampal activity correlated with various physiological and behavioral phenomena. Although analyzed by numerous investigators, during the last five decades, the mechanisms that lead to its generation still remain reason of debate. In the present report it is shown that hippocampal neurons, recorded from juvenile and adult slices, are endowed with intrinsic properties that allow the generation of a steady oscillatory activity. The frequency of this rhythmic ongoing process is highly sensitive to the level of the membrane potential, reaching values in the theta range, up to 6 Hz, for more depolarized values of membrane potential. Membrane potential oscillations are unmasked by loading pyramidal neurons with intracellular cesium, are sodium-independent, and are generated by the sequential activation of calcium and potassium conductances. Finally, like theta rhythm, regularly occurring membrane potential oscillations can be detected since postnatal day 10 and their frequency increases with age, i.e., during the following 2 weeks.

A pacemaker current in dye-coupled hilar interneurons contributes to the generation of giant GABAergic potentials in developing hippocampus.

The establishment of synaptic connections and their refinement during development require neural activity. Increasing evidence suggests that spontaneous bursts of neural activity within an immature network are mediated by gamma-aminobutyric acid via a paradoxical excitatory action. Our data show that in the developing hippocampus such synchronous burst activity is generated in the hilar region by transiently coupled cells. These cells have been identified as neuronal elements because they fire action potentials and they are not positive for the glial fibrillary acidic protein staining. Oscillations in hilar cells are "paced" by a hyperpolarization-activated current, with properties of Ih. Coactivated interneurons synchronously release GABA, which via its excitatory action may serve a neurotrophic function during the refinement of hippocampal circuitry.

Zinc modulation of bicuculline-sensitive and -insensitive GABA receptors in the developing rat hippocampus.

Intracellular recordings were used to study the effects of zinc on the bicuculline-sensitive and -insensitive responses evoked by GABA in CA3 rat hippocampal neurons in slices obtained from postnatal day (P) 0 to P8. In the absence of bicuculline, zinc inhibited GABA-induced responses in a concentration-dependent manner. This effect was developmentally regulated, being maximal (50%) between P0 and P5 and then declining to 30% after P5. In the presence of bicuculline, GABA-resistant responses were potentiated in 49% of cases, depressed in 38% and not affected in 13%. The period of maximum potentiation between P0 and P2 coincided with that of maximum expression of the bicuculline-resistant receptors. The effects of zinc were also studied using the whole-cell and outside-out configuration of the patch-clamp technique on bicuculline-sensitive and -insensitive GABA-induced currents elicited in isolated cells acutely dissociated from the same slices as those used for intracellular recordings. At a holding potential of -50 mV in symmetrical chloride solutions, GABA (50 and 100 microM) activated whole-cell inward currents which were reversibly blocked by zinc. The EC50 values for the blocking effect of zinc on currents evoked by 50 and 100 microM GABA were 6.6 nM and 5.8 microM respectively. In the presence of bicuculline (100 microM), zinc potentiated the residual responses to GABA; the response curve was bell-shaped with a peak at 1 microM. When the response to GABA was completely abolished by bicuculline, zinc (1 microM) was often able to restore it. In the presence of bicuculline, however, zinc was not able to restore the response to isoguvacine. In two excised outside-out patches, zinc (1 microM) increased the activity of opening of bicuculline-resistant GABA-evoked single channel currents (Np) from 1 to 1.87 and from 0.25 to 0.42 respectively, without changing single-channel conductance. These data suggest that down- or up-regulation of bicuculline-sensitive or -insensitive GABA receptors may be functionally important in regulating synaptic activity during development.

Cyclic AMP-dependent modulation of giant depolarizing potentials by metabotropic glutamate receptors in the rat hippocampus.

1. Intracellular recordings were used to study the role of metabotropic glutamate receptors (mGluRs) in modulating GABA-mediated giant depolarizing potentials (GDPs) in immature rat hippocampal CA3 neurones. 2. The mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM) reduced the frequency of GDPs. The broad-spectrum ionotropic glutamate receptor antagonist kynurenic acid (1 mM) blocked GDPs. 3. In the presence of kynurenic acid, both tetanic stimulation of the hilus or bath application of quisqualic acid (1 microM) and trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 20 microM) induced the appearance of GDPs. These effects were antagonized by MCPG (1 mM) or L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and blocked by bicuculline (10 microM). 4. 8-Bromo-cAMP (8-Br-cAMP, 0.3 mM), 3-isobutyl-1-methylxanthine (IBMX, 200 microM) or forskolin (30 microM) mimicked the effects of mGluR agonists on GDPs. The forskolin analogue 1,9-dideoxyforskolin (30 microM), which does not activate adenylate cyclase, was ineffective. 5. Incubation of slices in the presence of the protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS) (500 microM) or superfusion of Rp-cAMPS (20 microM) prevented the effects of forskolin or t-ACPD on GDPs. In the presence of kynurenic acid, the protein kinase C activator, phorbol 12,13-diacetate (2 microM) induced the appearance of GDPs. This effect was prevented by staurosporine (1 microM). However, staurosporine (1-3 microM) did not modify the effects of t-ACPD on GDPs. 6. It is suggested that, during development, mGluRs enhance the synchronous release of GABA, responsible for GDPs, through cAMP-dependent protein kinase.

Whole cell and single channel properties of a new GABA receptor transiently expressed in the Hippocampus.

1. The patch-clamp technique was used to characterize, in acutely dissociated CA3 rat hippocampal neurons, the whole cell and single channel properties of a novel response to gamma-aminobutyric acid (GABA) present only during a restricted period of postnatal development. 2. At postnatal days 0-10 (P0-P10), both GABA (100 microM) and isoguvacine (50 microM) evoked at a holding potential of -50 mV, in symmetrical chloride solution, whole cell inward currents. Bicuculline blocked the response to isoguvacine but only reduced the response to GABA (from 512 +/- 137 pA to 60 +/- 13 pA, mean +/- SE). After P12, bicuculline abolished the response to GABA. 3. The bicuculline-insensitive GABA currents were Cl- mediated and antagonized by picrotoxin. The desensitization rate was slower than the conventional bicuculline-sensitive response. The peak to plateau ratio induced by 0.1 or 1 mM of GABA shifted from 4.6 +/- 0.4 and 17.7 +/- 2.6 to 1.5 +/- 0.1 and 3.1 +/- 0.5 in the absence or in the presence of bicuculline, respectively. The recovery from desensitization was significantly faster for the bicuculline-insensitive responses. 4. In excised outside-out patches, GABA (20 microM) activated, in the presence of bicuculline (100 microM), single channel currents having conductances of 14, 22, and 31 pS. These values were similar to those obtained in the same preparation, in the absence of bicuculline. 5. These findings suggest that this new receptor type, which mediates bicuculline-insensitive responses with slow kinetics, may potentiate the depolarizing action of GABA during a critical period of postnatal development and therefore play a crucial role in synaptogenesis.

Transient expression of a novel type of GABA response in rat CA3 hippocampal neurones during development.

1. Intracellular recordings were used to study the effects of gamma-aminobutyric acid (GABA) on rat CA3 hippocampal neurones during the first two weeks of postnatal life. 2. In the presence of tetrodotoxin (TTX, 1 microM), from postnatal day 0 (P0) to P12 both associated with an increase in input conductance whereas baclofen (30-100 microM) produced a membrane hyperpolarization. 3. Bicuculline (50 microM) reduced the effects of GABA and abolished the response to isoguvacine without affecting the response to baclofen. 4. This novel bicuculline-insensitive GABA response was chloride dependent and was blocked by picrotoxin (10-100 microM) in an uncompetitive way. In bicuculline and picrotoxin, a GABAB-mediated hyperpolarization appeared. 5. Towards the end of the second postnatal week, bicuculline blocked the GABA-induced depolarization and revealed a small hyperpolarizing response which was blocked by the GABAB antagonist CGP 35348 (0.5-1 mM). 6. It is suggested that, during development, the GABA response was mediated through the conventional GABAA and GABAB receptors as well as a new bicuculline-baclofen-insensitive type of receptor.