Fabrizio Eusebi

Tumor necrosis factor alters synaptic transmission in rat hippocampal slices

The effects of human recombinant tumor necrosis factor (TNF-alpha) on the synaptic transmission were studied in rat hippocampal slices by using extracellular field potential recordings. Population spikes and/or excitatory postsynaptic potentials were extracellularly recorded in hippocampus CA1 region from stratum pyramidale and stratum radiatum, respectively, and synaptic transmission was examined in the Schaffer collateral/commissural-CA1 pathway. Basal neurotransmission slightly and promptly increased in slices acutely exposed to TNF-alpha (1-100 nM). Examination of the long-term potentiation (LTP) revealed that a brief treatment with the cytokine did not influence LTP, while a long-lasting application of TNF-alpha (50 min or more) inhibited LTP in a dose-dependent way in the range of 1-100 nM. A role for TNF-alpha as a peptide of immunological significance belonging to the family of brain neuromodulators is discussed.

CXC chemokines interleukin-8 (IL-8) and growth-related gene product α (GROα) modulate Purkinje neuron activity in mouse cerebellum

Abstract We give here evidence that Purkinje neurons (PNs) of mouse cerebellar slices studied with patch clamp technique combined with laser confocal microscopy, respond to human IL-8 and GROα by (i) a cytosolic Ca2+ transient compatible with inositol (1,4,5) trisphosphate (InsP3) formation; (ii) an enhancement of the neurotransmitter release; and (iii) an impairment of the long-term depression of synaptic strength (LTD). It was also found the expression of IL-8 receptor type 2 in PN and granule cells by immunofluorescence, immunoblotting and RT-PCR analysis. Considered together these findings suggest that IL-8 and GROα may play a neuromodulatory role on mouse cerebellum.

Interleukin-2 suppresses established long-term potentiation and inhibits its induction in the rat hippocampus

The effects of recombinant interleukin-2 (rIL-2) on the potentiation of the synaptic transmission were studied in rat hippocampal slices by using extracellular field potential recordings. The application of rIL-2 inhibited the induction of both short-term (STP) and long-term potentiation (LTP) in a dose-dependent manner. In addition, rIL-2 (1000 U/ml) reduced both post-tetanic potentiation (PTP) and LTP maintenance phase. The possible involvement of rIL-2 action on the synaptic potentiation with the enzymatic activity of protein kinase systems is discussed.

Chemokine CX3CL1 protects rat hippocampal neurons against glutamate-mediated excitotoxicity.

Excitotoxicity is a cell death caused by excessive exposure to glutamate (Glu), contributing to neuronal degeneration in many acute and chronic CNS diseases. We explored the role of fractalkine/CX3CL1 on survival of hippocampal neurons exposed to excitotoxic doses of Glu. We found that: CX3CL1 reduces excitotoxicity when co-applied with Glu, through the activation of the ERK1/2 and PI3K/Akt pathways, or administered up to 8 h after Glu insult; CX3CL1 reduces the Glu-activated whole-cell current through mechanisms dependent on intracellular Ca2+; CX3CL1 is released from hippocampal cells after excitotoxic insult, likely providing an endogenous protective mechanism against excitotoxic cell death.

SDF‐1α‐mediated modulation of synaptic transmission in rat cerebellum

The functional expression of the seven‐transmembrane domain G protein‐coupled chemokine receptor CXCR‐4/fusin in rat nerve cell was demonstrated by staining with a polyclonal anti‐CXCR‐4 Ab, and by evaluating the calcium responses to the physiological agonist stromal‐derived cell factor‐1α (SDF‐1α) in both cerebellar granule cells in culture and Purkinje neurons (PNs) in cerebellar slices. Cerebellar glial, granule and Purkinje cells showed a pronounced staining for CXCR‐4. Furthermore, cultured granule cells exhibited Ca2+ transients elicited by the application of SDF‐1α, both in cell bodies and in neuronal processes. Whole‐cell patch‐clamped PNs in cerebellar slices responded to SDF‐1α application by a slow inward current followed by an increase of both intracellular Ca2+ level and spontaneous synaptic activity. In particular, the SDF‐1α‐induced slow inward current was considerably reduced by ionotropic glutamate receptor blockers, but developed fully in a medium in which synaptic transmission was inhibited, indicating that this current might be, at least in part, mediated by extrasynaptic glutamate, possibly released from the surrounding glial and/or nerve cells. Taken together, these findings indicate a functional involvement of CXCR‐4 in the modulation of synaptic transmission, adding another member to the repertoire of the chemokine receptors exerting a neuromodulatory role in the cerebellum.

Golf putt outcomes are predicted by sensorimotor cerebral EEG rhythms

It is not known whether frontal cerebral rhythms of the two hemispheres are implicated in fine motor control and balance. To address this issue, electroencephalographic (EEG) and stabilometric recordings were simultaneously performed in 12 right‐handed expert golfers. The subjects were asked to stand upright on a stabilometric force platform placed at a golf green simulator while playing about 100 golf putts. Balance during the putts was indexed by body sway area. Cortical activity was indexed by the power reduction in spatially enhanced alpha (8–12 Hz) and beta (13–30 Hz) rhythms during movement, referred to as the pre‐movement period. It was found that the body sway area displayed similar values in the successful and unsuccessful putts. In contrast, the high‐frequency alpha power (about 10–12 Hz) was smaller in amplitude in the successful than in the unsuccessful putts over the frontal midline and the arm and hand region of the right primary sensorimotor area; the stronger the reduction of the alpha power, the smaller the error of the unsuccessful putts (i.e. distance from the hole). These results indicate that high‐frequency alpha rhythms over associative, premotor and non‐dominant primary sensorimotor areas subserve motor control and are predictive of the golfers performance.

Hippocampal volume and cortical sources of EEG alpha rhythms in mild cognitive impairment and Alzheimer disease

Atrophy of hippocampus and alteration of resting eyes-closed electroencephalographic (EEG) rhythms represent important features of mild cognitive impairment (MCI) and Alzheimers disease (AD). Here we evaluated linear and non-linear aspects of the relationship between these features in the continuum along MCI and AD conditions, as a reflection of neurodegenerative processes. Eyes-closed resting EEG data were recorded in 60 healthy elderly (Nold), 88 MCI, and 35 Alzheimers disease (AD) patients. Hippocampal volume was measured in magnetic resonance imaging of the MCI and AD subjects. Based on the normalized hippocampal volume, selected MCI subjects could be divided into two demographically paired sub-groups: those with larger hippocampal volume (MCI +h; N=40; mini mental state evaluation - MMSE - score=27.5+/-0.26 SE) and those with smaller hippocampal volume (MCI -h; N=40; h; MMSE=26.5+/-0.34 SE); the normalized hippocampal volume was statistically greater in the MCI +h than in the MCI -h and AD subjects (p<0.0001). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). Cortical EEG generators were estimated by LORETA software. Results showed that the power of occipital, parietal, and temporal alpha 1 sources was maximum in MCI +h, intermediate in MCI -h, and low in AD patients. Furthermore, the power of these sources was linearly and non-linearly correlated with the normalized hippocampal volume. These 3 EEG sources were given as input for evaluating correlations (linear, exponential, logarithmic and power) with hippocampal volume. When subjects were considered as a unique group, there was a significant linear correlation of hippocampal volume with the magnitude of alpha 1 sources in the parietal, occipital and temporal areas. In general, the EEG sources showing significant linear correlation with hippocampal volume also supported a non-linear correlation with hippocampal volume strongly for the logarithmic one. The present results suggest that progressive atrophy of hippocampus correlates with decreased cortical alpha power, as estimated by using LORETA source modeling, in the continuum along MCI and AD conditions.

Directionality of EEG synchronization in Alzheimer's disease subjects

Is directionality of electroencephalographic (EEG) synchronization abnormal in amnesic mild cognitive impairment (MCI) and Alzheimers disease (AD)? EEG data were recorded in 64 normal elderly (Nold), 69 amnesic MCI, and 73 mild AD subjects at rest condition (closed eyes). Direction of information flux within EEG functional coupling at electrode pairs was performed by directed transfer function (DTF) at delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10 Hz), alpha 2 (10-12 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz). Parietal to frontal direction of the information flux within EEG functional coupling was stronger in Nold than in MCI and/or AD subjects, namely for alpha and beta rhythms. In contrast, the directional flow within inter-hemispheric EEG functional coupling did not discriminate among the three groups. These results suggest that directionality of parieto-to-frontal EEG synchronization is abnormal not only in AD but also in amnesic MCI.

Resting EEG sources correlate with attentional span in mild cognitive impairment and Alzheimer's disease

Previous evidence has shown that resting delta and alpha electroencephalographic (EEG) rhythms are abnormal in patients with Alzheimers disease (AD) and its potential preclinical stage (mild cognitive impairment, MCI). Here, we tested the hypothesis that these EEG rhythms are correlated with memory and attention in the continuum across MCI and AD. Resting eyes‐closed EEG data were recorded in 34 MCI and 53 AD subjects. EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). EEG cortical sources were estimated by low‐resolution brain electromagnetic tomography (LORETA). These sources were correlated with neuropsychological measures such as Rey list immediate recall (word short‐term memory), Rey list delayed recall (word medium‐term memory), Digit span forward (immediate memory for digits probing focused attention), and Corsi span forward (visuo‐spatial immediate memory probing focused attention). A statistically significant negative correlation (Bonferroni corrected, P < 0.05) was observed between Corsi span forward score and amplitude of occipital or temporal delta sources across MCI and AD subjects. Furthermore, a positive correlation was shown between Digit span forward score and occipital alpha 1 sources (Bonferroni corrected, P < 0.05). These results suggest that cortical sources of resting delta and alpha rhythms correlate with neuropsychological measures of immediate memory based on focused attention in the continuum of MCI and AD subjects.

Chemokine Fractalkine/CX3CL1 Negatively Modulates Active Glutamatergic Synapses in Rat Hippocampal Neurons

We examined the effects of the chemokine fractalkine (CX3CL1) on EPSCs evoked by electrical stimulation of Schaffer collaterals in patch-clamped CA1 pyramidal neurons from rat hippocampal slices. Acute application of CX3CL1 caused a sustained reduction of EPSC amplitude, with partial recovery after washout. CX3CL1-induced EPSC depression is postsynaptic in nature, because paired-pulse ratio was maintained, amplitude distribution of spontaneous excitatory postsynaptic currents shifted to lower values, and whole-cell current responses to AMPA were reversibly inhibited. EPSC depression by CX3CL1 is mediated by CX3CL1 receptor (CX3CR1), because CX3CL1 was unable to influence EPSC amplitude in CA1 pyramidal neurons from CX3CR1 knock-out mice. CX3CL1-induced depression of both EPSC and AMPA current was not observed in the absence of afferent fiber stimulation or AMPA receptor activation, respectively, indicating the requirement of sustained receptor activity for its development. Findings obtained from hippocampal slices, cultured hippocampal neurons, and transfected human embryonic kidney cells indicate that a Ca2+-, cAMP-, and phosphatase-dependent process is likely to modulate CX3CL1 effects because of the following: (1) CX3CL1-induced depression was antagonized by intracellular BAPTA, 8Br-cAMP, phosphatase inhibitors, and pertussis toxin (PTX); (2) CX3CL1 inhibited forskolin-induced cAMP formation sensitive to PTX; and (3) CX3CL1 inhibited forskolin-induced Ser845 GluR1 phosphorylation, which was sensitive to PTX and dependent on Ca2+ and phosphatase activity. Together, these findings indicate that CX3CL1 negatively modulates AMPA receptor function at active glutamatergic synapses through cell-signaling pathways by influencing the balance between kinase and phosphatase activity.