Increasing attention is being paid to the role of inflammatory and immune molecules in the modulation of central nervous system (CNS) function. Tumour necrosis factor-α (TNF-α) is a pro-inflammatory cytokine, the receptors for which are expressed on neurones and glial cells throughout the CNS. Through the action of its two receptors, it has a broad range of actions on neurones which may be either neuroprotective or neurotoxic. It plays a facilitatory role in glutamate excitotoxicity, both directly and indirectly by inhibiting glial glutamate transporters on astrocytes. Additionally, TNF-α has direct effects on glutamate transmission, for example increasing expression of AMPA receptors on synapses. TNF-α also plays a role in synaptic plasticity, inhibiting long-term potentiation (LTP), a process dependent on p38 mitogen activated kinase (p38 MAP) kinase. In the following review we look at these and other effects of TNF-α in the CNS.

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Abstract-The pro-inflammatory cytokine tumor-necrosis factor-␣ (TNF-␣) is elevated in several neuropathologicalThis work suggests that TNF-␣ inhibition of LTP represents a biphasic response, a p38 MAPK-dependent phase that coincides with the early phase of LTP and a p38 MAPK independent phase that temporally maps to late LTP.

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SUMMARYApproximately 2.5 million people worldwide are clinically blind because of diabetic retinopathy. In the non-proliferative stage, the pathophysiology of this ocular manifestation of diabetes presents as morphological and functional disruption of the retinal vasculature, and dysfunction of retinal neurons. However, it is uncertain whether the vascular and neuronal changes are interdependent or independent events. In addition, the identity of the retinal neurons that are most susceptible to the hyperglycaemia associated with diabetes is unclear. Here, we characterise a novel model of non-proliferative diabetic retinopathy in adult zebrafish, in which the zebrafish were subjected to oscillating hyperglycaemia for 30 days. Visual function is diminished in hyperglycaemic fish. Significantly, hyperglycaemia disrupts cone photoreceptor neurons the most, as evidenced by prominent morphological degeneration and dysfunctional cone-mediated electroretinograms. Disturbances in the morphological integrity of the blood-retinal barrier were also evident. However, we demonstrate that these early vascular changes are not sufficient to induce cone photoreceptor dysfunction, suggesting that the vascular and neuronal complications in diabetic retinopathy can arise independently. Current treatments for diabetic retinopathy target the vascular complications. Our data suggest that cone photoreceptor dysfunction is a clinical hallmark of diabetic retinopathy and that the debilitating blindness associated with diabetic retinopathy may be halted by neuroprotection of cones.

The effects of the specific p42/44 mitogen-activated protein (MAP) kinase cascade inhibitor, PD98059, were investigated on three types of long-term potentiation (LTP) in the medial perforant path of the rat dentate gyrus in vitro: LTP induced by 1) high-frequency stimulation (HFS-LTP), 2) application for 10 min of the K+ channel blocker, tetraethylammonium chloride (TEA-LTP), and 3) application of the metabotropic glutamate receptor (mGluR) agonist (S)-dihydrophenylglycine (S-DHPG) for 2 min (DHPG-LTP). Bath perfusion of PD98059 (50 microM) for 1 h inhibited HFS-LTP (111 +/- 5%, mean +/- SE, at 90 min posttetanus in test slices compared with 144 +/- 5% in control slices; n = 6-7). Concentrations of 10 and 20 microM PD98059 had no effect on HFS-LTP (n = 6). PD98059 (50 microM) had no effect on the isolated N-methyl--aspartate excitatory postsynaptic potential (NMDA-EPSP) or on the maintenance phase of HFS-LTP. PD98059 (50 microM) did not affect paired-pulse depression (PPD; interstimulus intervals of 10 and 100 ms) of synaptic transmission as is typically observed in the medial perforant path of the dentate gyrus. Bath application of (S)-DHPG (40 microM) for 2 min gave rise to a potentiation of the EPSPs slope (148 +/- 4% at 1 h post-DHPG wash out; n = 5). Pretreatment of slices with PD98059 (50 microM) inhibited the DHPG-LTP (98 +/- 3% at 1 h post-DHPG wash out; n = 5). The TEA-LTP (125 +/- 4% at 1 h post-TEA wash out; n = 6) was found to be both -2-amino-5-phosphonopentanoic acid (-AP5; 100 microM) and nifedipine (20 microM) independent. However, the T type voltage-dependent calcium-channel blocker, NiCl2 (50 microM), completely inhibited the observed potentiation. The mGluR receptor antagonist alpha-methyl-4-carboxy-phenyl glycine (MCPG; 100 microM) and PD98059 (50 microM) caused a complete block of the TEA-LTP. These data show for the first time an involvement of the p42/44 MAP kinase in the induction and expression of both an NMDA-dependent and two forms of NMDA-independent LTP in the dentate gyrus.

Normal brain function is highly dependent on oxygen and nutrient supply and when the demand for oxygen exceeds its supply, hypoxia is induced. Acute episodes of hypoxia may cause a depression in synaptic activity in many brain regions, whilst prolonged exposure to hypoxia leads to neuronal cell loss and death. Acute inadequate oxygen supply may cause anaerobic metabolism and increased respiration in an attempt to increase oxygen intake whilst chronic hypoxia may give rise to angiogenesis and erythropoiesis in order to promote oxygen delivery to peripheral tissues. The effects of hypoxia on neuronal tissue are exacerbated by the release of many inflammatory agents from glia and neuronal cells. Cytokines, such as TNF-α, and IL-1β are known to be released during the early stages of hypoxia, causing either local or systemic inflammation, which can result in cell death. Another growing body of evidence suggests that inflammation can result in neuroprotection, such as preconditioning to cerebral ischemia, causing ischemic tolerance. In the following review we discuss the effects of acute and chronic hypoxia and the release of pro-inflammatory cytokines on synaptic transmission and plasticity in the central nervous system. Specifically we discuss the effects of the pro-inflammatory agent TNF-α during a hypoxic event.