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Calcium is a key signaling ion for induction of synaptic plasticity processes that are believed to influence cognition. Mechanisms regulating activity-induced increases in neuronal calcium and related synaptic modifications are not fully understood. Moreover, involvement of specific synapses in discrete aspects of spatial learning remains to be elucidated. We used herpes simplex amplicons to overexpress calbindin D28k (CaBP) selectively in dentate gyrus (DG) granule cells. We then examined the effects on hippocampal network activity by recording evoked synaptic responses in vivo and in vitro and analyzing hippocampal-dependent behavior. Relative to Lac-Z- and sham-infected controls, CaBP overexpression increased mossy fiber (MF-CA3) excitatory postsynaptic potentials and reduced paired-pulse facilitation (PPF), suggesting an increase in presynaptic strength. Additionally, CaBP overexpression reduced long-term potentiation (LTP), caused a frequency-dependent inhibition of post-tetanic potentiation (PTP), and impaired spatial navigation. Thus, increasing CaBP levels selectively in the DG disrupts MF-CA3 presynaptic function and impairs spatial cognition. The results demonstrate the power of gene delivery in the study of the neural substrates of learning and memory and suggest that mossy fiber synaptic plasticity is critical for long-term spatial memory. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

GP120 (the protein component of the HIV viral coat) is neurotoxic and may contribute to the cell loss associated with AIDS-related dementia. Previously, it has been shown in rat cortical mixed cultures that gp120 increased the accumulation of hydrogen peroxide and superoxide, two reactive oxygen species (ROS). We now demonstrate that gp120 increased activity of the key antioxidant glutathione peroxidase (GSPx), presumably as a defensive mechanism against the increased ROS load. Both estrogen and glucocorticoids (GCs), the adrenal steroid released during stress, blunted this gp120 effect on GSPx activity. The similar effects of estrogen and of GCs are superficially surprising, given prior demonstrations that GCs exacerbated and estrogens protected against gp120 neurotoxicity. We find that these similar effects of estrogen and GCs on GSPx regulation arose, in fact, from very different routes, which are commensurate with these prior reports. Specifically, estrogen has demonstrated antioxidant properties that may prevent the ROS increase (therefore acting as a neuroprotective agent) and rendered unnecessary the compensatory GSPx increased activity. To verify this we have added H[sub 2]O[sub 2] to estrogen + gp120-treated cells, and GSPx activity was increased. However, with addition of H[sub 2]O[sub 2] to GCs + gp120-treated cells there was no increase in activity. GCs appeared to decrease enzyme production and or activity and therefore under insult conditions ROS levels rose in the cell resulting in increased neurotoxicity. Overexpression of GSPx enzyme via herpes vector system reversed the GCs-induced loss of enzyme and eliminated the GCs exacerbation of gp120 neurotoxicity. [ABSTRACT FROM AUTHOR]

Studies utilizing gene delivery to the nervous system indicate that various strategies are protective following acute neurological insults such as seizure and stroke. We have found that inhibitors of apoptosis are protective against excitotoxicity and heat stress but not energetic impairment in vitro. Here we studied the neuroprotective efficacy in vivo of these mediators: viral genes (crmA, p35, γ34.5 KsBcl-2) that have evolved to suppress suicidal host responses to infection, by inhibiting apoptosis. We investigated these effects by utilizing modified herpes vectors to deliver the anti-apoptotic agents intracerebraily and examined them in the face of excitotoxic and metabolic insults. We found that p35 and γ34.5 reduced by 45% a hippocampal CA3 lesion caused by kainic acid, while crmA and KsBci-2 did not. None of the inhibitors protected the dentate gyrus of the hippocampus following 3-acetylpyridine, a hypoglycemia model, but we found crmA to worsen the damage. These data are similar to our results in neuronal cultures where the inhibitors protected against the excitotoxin domoic acid, but not against the metabolic poison, cyanide. Together, the results suggest that inhibitors of various apoptotic elements are capable of protecting under acute insult conditions both in vitro and in vivo, suggesting possible future therapeutic applications. [ABSTRACT FROM AUTHOR]

The cellular events mediating necrotic neuron death are now reasonably well understood, and involve excessive extracellular accumulation of glutamate and free cytosolic calcium. When such necrotic neurological insults occur, neurons are not passively buffeted, but instead mobilize a variety of defenses in an attempt to decrease the likelihood of neuron death, or to decrease the harm to neighboring neurons (by decreasing the likelihood of inflammation). This review considers some of these defenses, organizing them along the lines of those which decrease neuronal excitability, decrease extracellular glutamate accumulation, decrease cytosolic calcium mobilization, decrease calcium-dependent degenerative events, enhance neuronal energetics, and bias a neuron towards apoptotic, rather than necrotic, death. Although these are currently perceived as a disparate array of cellular adaptations, some experimental approaches are suggested that may help form a more unified subdiscipline of cellular defenses against neurological insults. Such an advance would help pave the way for the rational design of therapeutic interventions against necrotic insults. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type-1 (HSV) amplicon vectors containing neuroprotective genes can alter cell physiology and enhance survival following various insults. However, to date, little is known about effects of viral infection itself (independent of the gene delivered) on neuronal physiology. Electrically-evoked synaptic responses are routinely recorded to measure functional alterations in the nervous system and were used here to assess the potential capability of HSV vectors to disrupt physiology of the hippocampus (a forebrain structure involved in learning that is highly susceptible to necrotic insult, making it a frequent target in gene therapy research). Population excitatory post-synaptic potentials (EPSPs) were recorded in the dentate gyrus (DG) and in area CA3 in vivo 72 h after infusion of an HSV vector expressing a reporter gene (lacZ) or vehicle into the DG. Evoked perforant path (PP-DG) or mossy fiber (MF-CA3) EPSPs slope values measured across input/output (I/O) curves were not altered by infection. Paired-pulse facilitation at either recording site was also unaffected. X-gal-positive granule cells surrounded the recording electrode (PP-DG recording) and stimulating electrode tracts (MF-CA3 recording) in animals that received vector, suggesting that we had measured function, at least in part, in infected neurons. Because of the negative electrophysiological result, we sought to deliver a gene with an HSV amplicon which would affect the measured endpoints, as a positive control. Delivery of calbindin D28kpotentiated PP-DG synaptic strength, indicating that our recording system could detect alterations due to vector expression. Thus, the data indicate that HSV vectors are benign, in regard to effects on synaptic function, and support the use of these vectors as a safe method to deliver selected genes to the central nervous system. [ABSTRACT FROM AUTHOR]

Presents abstract of several studies on mental illness. Prevalence of serious mental illness; Association between hypercortisolaemia and impaired cognitive performance before treatment for Cushing's syndrome; Discussion on gene therapy for psychiatric disorders.