The effects of electrical hippocampal kindling of seizures on amino acids and kynurenic acid concentrations in brain structures

Our study demonstrated that the development of seizures during the electrically induced kindling of seizures is associated with significant changes in the concentration of kynurenic acid (KYNA) and its precursor, tryptophan (TRP). The primary finding of our study was an increase in KYNA levels and the KYNA/TRP ratio (a theoretical index of activity of the kynurenine pathway) in the amygdala and hippocampus of kindled animals. We also found decreases in the concentration of tryptophan in the hippocampus and prefrontal cortex. Changes in the concentration of KYNA and TRP in the amygdala were accompanied by a significant decrease in γ-Aminobutryic Acid (GABA) levels and an increase in the glutamate/GABA ratio. Moreover, we found a significant negative correlation between the local concentrations of KYNA and glutamate in the amygdala of kindled rats. However, there were no changes in the local concentrations of the following amino acids: glutamate, aspartate, glutamine, glycine, taurine and alanine. In conclusion, these new results suggest a modulatory influence of KYNA on the process of epileptogenesis, characterized by a negative relationship between the KYNA and glutamate systems in the amygdala

Hippocampal Desynchronization of Functional Connectivity Prior to the Onset of Status Epilepticus in Pilocarpine-Treated Rats

Status epilepticus (SE), a pro-epileptogenic brain insult in rodent models of temporal lobe epilepsy, is successfully induced by pilocarpine in some, but not all, rats. This study aimed to identify characteristic alterations within the hippocampal neural network prior to the onset of SE. Sixteen microwire electrodes were implanted into the left hippocampus of male Sprague-Dawley rats. After a 7-day recovery period, animal behavior, hippocampal neuronal ensemble activities, and local field potentials (LFP) were recorded before and after an intra-peritoneal injection of pilocarpine (350 mg/kg). The single-neuron firing, population neuronal correlation, and coincident firing between neurons were compared between SE (n = 9) and nonSE rats (n = 12). A significant decrease in the strength of functional connectivity prior to the onset of SE, as measured by changes in coincident spike timing between pairs of hippocampal neurons, was exclusively found in SE rats. However, single-neuron firing and LFP profiles did not show a significant difference between SE and nonSE rats. These results suggest that desynchronization in the functional circuitry of the hippocampus, likely associated with a change in synaptic strength, may serve as an electrophysiological marker prior to SE in pilocarpine-treated rats

Tryptophan Scanning Analysis of the Membrane Domain of CTR-Copper Transporters

Membrane proteins of the CTR family mediate cellular copper uptake in all eukaryotic cells and have been shown to participate in uptake of platinum-based anticancer drugs. Despite their importance for life and the clinical treatment of malignancies, directed biochemical studies of CTR proteins have been difficult because high-resolution structural information is missing. Building on our recent 7Å structure of the human copper transporter hCTR1, we present the results of an extensive tryptophan-scanning analysis of hCTR1 and its distant relative, yeast CTR3. The comparative analysis supports our previous assignment of the transmembrane helices and shows that most functionally and structurally important residues are clustered around the threefold axis of CTR trimers or engage in helix packing interactions. The scan also identified residues that may play roles in interactions between CTR trimers and suggested that the first transmembrane helix serves as an adaptor that allows evolutionarily diverse CTRs to adopt the same overall structure. Together with previous biochemical and biophysical data, the results of the tryptophan scan are consistent with a mechanistic model in which copper transport occurs along the center of the trimer

Hippocampal-Dependent Spatial Memory in the Water Maze is Preserved in an Experimental Model of Temporal Lobe Epilepsy in Rats

Cognitive impairment is a major concern in temporal lobe epilepsy (TLE). While different experimental models have been used to characterize TLE-related cognitive deficits, little is known on whether a particular deficit is more associated with the underlying brain injuries than with the epileptic condition per se. Here, we look at the relationship between the pattern of brain damage and spatial memory deficits in two chronic models of TLE (lithium-pilocarpine, LIP and kainic acid, KA) from two different rat strains (Wistar and Sprague-Dawley) using the Morris water maze and the elevated plus maze in combination with MRI imaging and post-morten neuronal immunostaining. We found fundamental differences between LIP- and KA-treated epileptic rats regarding spatial memory deficits and anxiety. LIP-treated animals from both strains showed significant impairment in the acquisition and retention of spatial memory, and were unable to learn a cued version of the task. In contrast, KA-treated rats were differently affected. Sprague-Dawley KA-treated rats learned less efficiently than Wistar KA-treated animals, which performed similar to control rats in the acquisition and in a probe trial testing for spatial memory. Different anxiety levels and the extension of brain lesions affecting the hippocampus and the amydgala concur with spatial memory deficits observed in epileptic rats. Hence, our results suggest that hippocampal-dependent spatial memory is not necessarily affected in TLE and that comorbidity between spatial deficits and anxiety is more related with the underlying brain lesions than with the epileptic condition per se