Tamás Farkas

Activation of the primary motor cortex by somatosensory stimulation in adult rats is mediated mainly by associational connections from the somatosensory cortex

In anaesthetized adult rats, facial nerve injury causes a disinhibition of the interhemispheric connections between homotopic representation fields in the primary motor cortex with a latency of 4 min (Toldi et al., 1996, Neurosci Lett. 203, 179-182). One possible explanation for the induction of such rapid changes is an alteration of the somatosensory input to the motor cortex. To test this hypothesis, unit activity in primary motor cortex was recorded during electrical stimulation of trigeminal afferents in the contralateral whisker-pad. About one-third of all recorded primary motor cortex neurons responded with latencies shorter than in the ventrolateral and posterior nuclei of the thalamus. Responses failed at stimulation frequencies > or = 10 Hz and after elimination or inactivation of the somatosensory cortex. Within primary motor cortex, the activatable neurons displayed a bilaminar distribution and were identified as pyramidal neurons by neurobiotin labelling. The results suggest that trigeminal afferents participate in modulation of the activity of primary motor cortex output neurons via primary somatosensory cortex-to-primary motor cortex associational connections, even under anaesthesia.

Non-fibrillar β-amyloid abates spike-timing-dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors

Cognitive decline in Alzheimers disease (AD) stems from the progressive dysfunction of synaptic connections within cortical neuronal microcircuits. Recently, soluble amyloid β protein oligomers (Aβols) have been identified as critical triggers for early synaptic disorganization. However, it remains unknown whether a deficit of Hebbian‐related synaptic plasticity occurs during the early phase of AD. Therefore, we studied whether age‐dependent Aβ accumulation affects the induction of spike‐timing‐dependent synaptic potentiation at excitatory synapses on neocortical layer 2/3 (L2/3) pyramidal cells in the APPswe/PS1dE9 transgenic mouse model of AD. Synaptic potentiation at excitatory synapses onto L2/3 pyramidal cells was significantly reduced at the onset of Aβ pathology and was virtually absent in mice with advanced Aβ burden. A decreased α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA)/N‐methyl‐d‐aspartate (NMDA) receptor‐mediated current ratio implicated postsynaptic mechanisms underlying Aβ synaptotoxicity. The integral role of Aβols in these processes was verified by showing that pretreatment of cortical slices with Aβ(25−35)ols disrupted spike‐timing‐dependent synaptic potentiation at unitary connections between L2/3 pyramidal cells, and reduced the amplitude of miniature excitatory postsynaptic currents therein. A robust decrement of AMPA, but not NMDA, receptor‐mediated currents in nucleated patches from L2/3 pyramidal cells confirmed that Aβols perturb basal glutamatergic synaptic transmission by affecting postsynaptic AMPA receptors. Inhibition of AMPA receptor desensitization by cyclothiazide significantly increased the amplitude of excitatory postsynaptic potentials evoked by afferent stimulation, and rescued synaptic plasticity even in mice with pronounced Aβ pathology. We propose that soluble Aβols trigger the diminution of synaptic plasticity in neocortical pyramidal cell networks during early stages of AD pathogenesis by preferentially targeting postsynaptic AMPA receptors.

Neonatal enucleation induces cross-modal changes in the barrel cortex of rat. A behavioural and electrophysiological study

The present study was undertaken to determine whether neonatal enucleation leads to functional changes in the somato-sensory system and whether it has any behavioural effects. Binocular enucleation was performed on newborn rats. The effects of enucleation were tested versus controls in a rectangular maze on 10 successive days starting on postnatal day 80. Immediately after the 10-day behavioural study session, electro-physiological experiments were performed on 5 enucleated and 5 control rats. All the whiskers of the remaining animals were clipped off on both sides, and these animals continued the maze running for four additional sessions. The behavioural study demonstrated that the maze performance achieved by the neonatally enucleated animals was better than that of the controls. This suggested that cross-modal compensatory changes took place in other sensory systems, presumably somatosensory too. This was supported by the result of the experiment preceded by bilateral vibrissa clipping. The electrophysiological experiments clearly revealed that functional changes took place in the somatosensory system of enucleated rats. In these animals, the cells in some barrels (C1 and E3) displayed enlarged receptive fields, while in an other barrel (A3) an increased angular sensitivity for deflection of its related whisker was observed. This combined study clearly demonstrates that neonatal enucleation is able to induce cross-modal compensatory changes in the somatosensory system of the rat.

Kynurenine administered together with probenecid markedly inhibits pentylenetetrazol-induced seizures. An electrophysiological and behavioural study

The kynurenine pathway converts tryptophan into various compounds, including l-kynurenine, which in turn can be converted to the excitatory amino acid receptor antagonist kynurenic acid, which may therefore serve as a protective agent in such neurological disorders as epileptic seizures. Kynurenic acid, however, has a very limited ability to cross the blood-brain barrier, whereas kynurenine passes the barrier easily. In this study, we tested the hypothesis that kynurenine administered systemically together with probenecid, which inhibits kynurenic acid excretion from the cerebrospinal fluid, results in an increased level of kynurenic acid in the brain that is sufficiently high to provide protection against the development of pentylentetrazol-induced epileptic seizures. CA3 stimulation-evoked population spike activity was recorded from the pyramidal layer of area CA1 of the rat hippocampus, and in another series of behavioural experiments, water maze and open-field studies were carried out to test the presumed protective effect of kynurenine + probenecid pre-treatment against pentylenetetrazol-induced seizures. This study has furnished the first electrophysiological proof that systemic kynurenine (300 mg/kg, i.p.) and probenecid (200 mg/kg, i.p.) administration protects against pentylenetetrazol-induced (60 mg/kg, i.p.) epileptic seizures.

Kynurenine diminishes the ischemia-induced histological and electrophysiological deficits in the rat hippocampus

The neuroprotective effect of L-kynurenine sulfate (KYN), a precursor of kynurenic acid (KYNA, a selective N-methyl-D-aspartate receptor antagonist), was studied. KYN (300 mg/kg i.p., applied daily for 5 days) appreciably decreased the number of injured pyramidal cells from 1850+/-100/mm(2) to 1000+/-300/mm(2) (p<0.001) in the CA1 region of the hippocampus in the four-vessel occlusion (4VO)-induced ischemic adult rat brain. A parallel increase in the number of intact, surviving neurons was demonstrated. Post-treatment with KYN (applied immediately right after reperfusion) proved to be much less effective. In parallel with the histology, a protective effect of KYN on the functioning of the CA1 region was observed: long-term potentiation was abolished in the 4VO animals, but its level and duration were restored by pretreatment with KYN. It is concluded that the administration of KYN elevates the KYNA concentration in the brain to neuroprotective levels, suggesting its potential clinical usefulness for the prevention of neuronal loss in neurodegenerative diseases.

Facial nerve injury‐induced disinhibition in the primary motor cortices of both hemispheres

Unilateral facial nerve transection induces plastic reorganization of the somatotopic order in the primary motor cortex area (MI). This process is biphasic and starts with a transient disinhibition of connections between cortical areas in both hemispheres. Little is known about the underlying mechanisms. Here, cortical excitability has been studied by paired pulse electrical stimulation, applied either within the MI or peripherally to the trigeminal nerve, while the responses were recorded bilaterally in the MI. The ratios between the amplitudes of the second and first evoked potentials (EPs or fEPSPs) were taken as measures of the inhibitory capacity in the MI ipsilateral or contralateral to the nerve injury. A skin wound or unilateral facial nerve exposure immediately caused a transient facilitation, which was followed by a reset to some level of inhibition in the MI on both sides. After facial nerve transection, the first relatively mild reduction of inhibition started shortly (within 10 min) after denervation. This was followed by a second step, involving a stronger decrease in inhibition, 40–45 min later. Previous publications have proved that sensory nerve injury (deafferentation) induces disinhibition in corresponding areas of the sensory cortex. It is now demonstrated that sham operation and, to an even greater extent, unilateral transection of the purely motoric facial nerve (deefferentation), each induce extended disinhibition in the MIs on both sides.

Neuroprotection with a new kynurenic acid analog in the four-vessel occlusion model of ischemia

Global forebrain ischemia results in damage to the pyramids in the CA1 hippocampal subfield, which is particularly vulnerable to excitotoxic processes. Morphological and functional disintegration of this area leads to a cognitive dysfunction and neuropsychiatric disorders. Treatment with N-methyl-d-aspartate receptor antagonists is a widely accepted method with which to stop the advance of excitotoxic processes and concomitant neuronal death. From a clinical aspect, competitive glycine- and polyamine-site antagonists with relatively low affinity and moderate side-effects are taken into account. Endogenous kynurenic acid acts as an antagonist on the obligatory co-agonist glycine site, and has long been at the focus of neuroprotective trials. In the present study, we estimated the neuroprotective capability of a novel kynurenic acid analog in transient global forebrain ischemia, measuring the rate of hippocampal CA1 pyramidal cell loss and the preservation of long-term potentiation at Schaffer collateral-CA1 synapses. The neuroprotective potential was reflected by a significantly diminished hippocampal CA1 cell loss and preserved long-term potentiation expression. The neuroprotective effect was robust in the event of pretreatment, and also when the drug was administered at the time of reperfusion. This result is beneficial since a putative neuroprotectant proven to be effective as post-treatment is of much greater benefit.

A novel kynurenic acid analogue: a comparison with kynurenic acid. An in vitro electrophysiological study

Kynurenic acid is an endogenous product of the tryptophan metabolism, and as a broad-spectrum antagonist of excitatory amino acid receptors may serve as a protective agent in neurological disorders. The use of kynurenic acid as a neuroprotective agent is rather limited, however, because it has only restricted ability to cross the blood–brain barrier. Accordingly, new kynurenic acid analogues which can readily cross the blood–brain barrier and exert their complex anti-excitotoxic activity are greatly needed. Such a novel analogue, 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride, has been developed and tested. In an in vitro electrophysiological study, in which its properties were compared with those of kynurenic acid, the new analogue behaved quite similarly to kynurenic acid: in the micromolar range, its administration led to a decrease in the amplitudes of the field excitatory postsynaptic potentials in the CA1 region of the hippocampus, while in nanomolar concentrations it did not give rise to inhibition, but, in fact, facilitated the field excitatory postsynaptic potentials. Moreover, the new analogue demonstrated similar protective action against PTZ-induced facilitation to that observed after kynurenic acid administration. The findings strongly suggest that the neuroactive effects of the new analogue are comparable with those of kynurenic acid, but, in contrast with kynurenic acid, it readily crosses the blood–brain barrier. The new analogue may therefore be considered a promising candidate for clinical studies.

Cross-modal plasticity of the corticothalamic circuits in rats enucleated on the first postnatal day

Reorganization of the reciprocal corticothalamic connections was studied as a possible anatomical substrate of the cross‐modal compensation of the missing visual input of the visual cortex by somatosensory‐evoked activities in neonatally enucleated rats. The use of quantitative retrograde tract‐tracing techniques revealed that the contribution of the lateral posterior thalamic nucleus (LP) is significantly increased following enucleation, while that of the dorsolateral geniculate and the lateral dorsal nuclei is decreased in the thalamocortical afferentation of a region in visual cortical area 17. In contrast with the control rats, a dense terminal arborization of afferents was labelled in the LP after the injection of anterograde tracer into the barrel cortex of the enucleated rats. The injection of anterograde tracer into the visual cortex also demonstrated a massive afferentation into the LP of the enucleated rats. Visual and somatosensory corticothalamic afferents exhibited similar ultrastructural features in the LP after enucleation, but their synaptic organizations differed as regards the diameter of the postsynaptic dendrites. Taken together with the previous observations, these results suggest a central role for the LP in the transmission of the somatosensory‐evoked activities to the visual cortex after early blindness.

Oxaloacetate restores the long-term potentiation impaired in rat hippocampus CA1 region by 2-vessel occlusion

Various acute brain pathological conditions are characterized by the presence of elevated glutamate concentrations in the brain interstitial fluids. It has been established that a decrease in the blood glutamate level enhances the brain-to-blood efflux of glutamate, removal of which from the brain may prevent glutamate excitotoxicity and its contribution to the long-lasting neurological deficits seen in stroke. A decrease in blood glutamate level can be achieved by exploiting the glutamate-scavenging properties of the blood-resident enzyme glutamate-oxaloacetate transaminase, which transforms glutamate into 2-ketoglutarate in the presence of the glutamate co-substrate oxaloacetate. The present study had the aim of an evaluation of the effects of the blood glutamate scavenger oxaloacetate on the impaired long-term potentiation (LTP) induced in the 2-vessel occlusion ischaemic model in rat. Transient (30-min) incomplete forebrain ischaemia was produced 72 h before LTP induction. Although the short transient brain hypoperfusion did not induce histologically identifiable injuries in the CA1 region (Fluoro-Jade B, S-100 and cresyl violet), it resulted in an impaired LTP function in the hippocampal CA1 region without damaging the basal synaptic transmission between the Schaffer collaterals and the pyramidal neurons. This impairment could be fended off in a dose-dependent manner by the intravenous administration of oxaloacetate in saline (at doses between 1.5 mmol and 0.1 mumol) immediately after the transient hypoperfusion. Our results suggest that oxaloacetate-mediated blood and brain glutamate scavenging contributes to the restoration of the LTP after its impairment by brain ischaemia.