Loss Of Functional Inhibition Research Articles

Rbap48 Could Act as a Candidate Biological Predictor for the Cognition Impairments of Patients with Temporal Lobe Epilepsy: A Hypothesis Based on Recent Molecular Findings

The temporal lobe epilepsy (TLE) is characterized by the neurodegeneration, abnormal reorganization of circuitry, and the loss of functional inhibition in hippocampus regions. Particularly, the declined neurogenesis in hippocampus has emerged as a significant hallmark of TLE. RbAp48, which is initially recognized as a retinoblastoma binding protein, is also identified as a positive regulator of human neurogenesis owing to its ability to regulate the expression of the pluripotency, differentiation, and cell cycle genes in human PSCs. The deficiency of RbAp48 critically contributes to the dentate gyrus (DG) dysfunction and is closely related to age-related memory deficits. Nevertheless, the roles of RbAp48 in the neurogenesis deterioration and memory loss of TLE patients remain to be determined. In view of the linkage between the deficiency of RbAp48 and the TLE-related memory loss, it is reasonable to hypothesize that the expression level of RbAp48 in the hippocampus of the TLE patients might be down regulated in accordance with the reduced neurogenesis. As the neurogenesis exhibits a close relationship with the hippocampal functions like learning and memory, the RbAp48 would possibly act as a candidate biology predictor for the cognition impairments of the TLE patients. This notion might cast insights into the etiology of hippocampusbased memory loss in TLE patients with the potentials of opening up new therapeutic avenues.

ClC-2 contributes to tonic inhibition mediated by α5 subunit-containing GABAA receptor in experimental temporal lobe epilepsy

Temporal lobe epilepsy (TLE), characterized by spontaneous recurrent seizures, learning and memory impairments is associated with neurodegeneration, abnormal reorganization of the circuitry and loss of functional inhibition in hippocampus. In adult hippocampus, the GABAergic cells mediate the major inhibitory function of the principal neurons, promoting the Cl(-) entry through the GABA(A) receptor, whether through phasic (synaptic) or tonic (extrasynaptic) conductance. Aside from classical synaptic component, tonic GABAergic inhibition mediated by extrasynaptic GABA(A) receptor received increasing attention over the past years. There is growing evidence that tonic inhibition plays an important role in epilepsy, memory and cognition. Since GABA(A) receptor-mediated inhibition depends on the maintenance of intracellular Cl(-) concentration at low levels in mature neurons, a shift in E(cl) is likely to participate in the generation and not merely a consequence of TLE. As we know, chloride channel-2 (ClC-2) is a member of the supergene family of voltage-gated chloride channels, it constitutes part of the background conductance and is involved in chloride extrusion. Here we show that ClC-2 were upregulated functionally in CA1 pyramidal cells in pilocarpine-treated rats, and that an observed increase in ClC-2 currents in CA1 pyramidal cells was reversed by L655,708, a specific antagonist of α5 subunit-containing GABA(A) receptor.

Implications of decreased hippocampal neurogenesis in chronic temporal lobe epilepsy

Temporal lobe epilepsy (TLE), characterized by spontaneous recurrent motor seizures (SRMS), learning and memory impairments, and depression, is associated with neurodegeneration, abnormal reorganization of the circuitry, and loss of functional inhibition in the hippocampal and extrahippocampal regions. Over the last decade, abnormal neurogenesis in the dentate gyrus (DG) has emerged as another hallmark of TLE. Increased DG neurogenesis and recruitment of newly born neurons into the epileptogenic hippocampal circuitry is a characteristic phenomenon occurring during the early phase after the initial precipitating injury such as status epilepticus. However, the chronic phase of the disease displays substantially declined DG neurogenesis, which is associated with SRMS, learning and memory impairments, and depression. This review focuses on DG neurogenesis in the chronic phase of TLE and first confers the extent and mechanisms of declined DG neurogenesis in chronic TLE. The available data on production, survival and neuronal fate choice decision of newly born cells, stability of hippocampal stem cell numbers, and changes in the hippocampal microenvironment in chronic TLE are considered. The next section discusses the possible contribution of declined DG neurogenesis to the pathophysiology of chronic TLE, which includes its potential effects on spontaneous recurrent seizures, cognitive dysfunction, and depression. The subsequent section considers strategies that may be useful for augmenting DG neurogenesis in chronic TLE, which encompass stem cell grafting, administration of distinct neurotrophic factors, physical exercise, exposure to enriched environment, and antidepressant therapy. The final section suggests possible ramifications of increasing the DG neurogenesis in chronic epilepsy.

Consequences of unilateral hearing loss: Cortical adjustment to unilateral deprivation

The effect of unilateral hearing loss on 2-deoxyglucose (2-DG) uptake in the central auditory system was studied in postnatal day 21 gerbils. Three weeks following a unilateral conductive hearing loss (CHL) or cochlear ablation (CA), animals were injected with 2-DG and exposed to an alternating auditory stimulus (1 and 2 kHz tones). Uptake of 2-DG was measured in the inferior colliculus (IC), medial geniculate (MG), and auditory cortex (fields AI and AAF) of both sides of the brain in experimental animals and in anesthesia-only sham animals (SH). Significant differences in uptake, compared to SH, were found in the IC contralateral to the manipulated ear (CHL or CA) and in AAF contralateral to the CHL ear. We hypothesize that these findings may result from loss of functional inhibition in the IC contralateral to CA, but not CHL. Altered states of inhibition at the IC may affect activity in pathways ascending to auditory cortex, and ultimately activity in auditory cortex itself. Altered levels of activity in auditory cortex may explain some auditory processing deficits experienced by individuals with CHL.

Fetal Hippocampal Grafts Containing CA3 Cells Restore Host Hippocampal Glutamate Decarboxylase-Positive Interneuron Numbers in a Rat Model of Temporal Lobe Epilepsy

Degeneration of CA3-pyramidal neurons in hippocampus after intracerebroventricular kainic acid (KA) administration, a model of temporal lobe epilepsy, results in hyperexcitability within both dentate gyrus and the CA1 subfield. It also leads to persistent reductions in hippocampal glutamate decarboxylase (GAD) interneuron numbers without diminution in Nissl-stained interneuron numbers, indicating loss of GAD expression in a majority of interneurons. We hypothesize that enduring loss of GAD expression in hippocampal interneurons after intracerebroventricular KA is attributable to degeneration of their CA3 afferent input; therefore, fetal CA3 grafts can restore GAD interneuron numbers through graft axon reinnervation of the host. We analyzed GAD interneuron density in the adult rat hippocampus at 6 months after KA administration after grafting of fetal mixed hippocampal, CA3 or CA1 cells into the CA3 region at 45 d after lesion, in comparison with "lesion-only" and intact hippocampus. In dentate and CA1 regions of the lesioned hippocampus receiving grafts of either mixed hippocampal or CA3 cells, GAD interneuron density was both significantly greater than lesion-only hippocampus and comparable with the intact hippocampus. In the CA3 region, GAD interneuron density was significantly greater than lesion-only hippocampus but less than the intact hippocampus. Collectively, the overall GAD interneuron density in the lesioned hippocampus receiving either mixed hippocampal or CA3 grafts was restored to that in the intact hippocampus. In contrast, GADinterneuron density in the lesioned hippocampus receiving CA1 grafts remained comparable with lesion-only hippocampus. Thus, grafts containing CA3 cells restore CA3 lesion-induced depletions in hippocampal GAD interneurons, likely by reinnervation of GAD-deficient interneurons. This specific graft-mediated effect is beneficial because reactivation of interneurons could ameliorate both loss of functional inhibition and hyperexcitability in CA3-lesioned hippocampus.

Function of synapses in the CA1 region of the hippocampus: Their contribution to the generation or control of epileptiform activity

1. 1. In the kainic acid lesioned hippocampus there is a loss of functional inhibition that is associated with reduction of the IPSPs recorded intracellularly from the surviving CA1 pyramidal cells. The possible pre- or postsynaptic origin of this change has been investigated. 2. 2. Iontophoretic application of GABA to the soma and dendrites of CA1 pyramidal cells indicated that there had been no change in the efficacy of the postsynaptic GABA receptors on these cells. 3. 3. Although a pre-synaptic mechanism is implicated, at one week post lesion we were unable to find any difference in the Ca + dependent K + evoked release of endogenous GABA. However, at survival times greater than 1 week immunohistological studies showed a decrease in the number of somatostatin positive non-pyramidal cells in the stratum oriens of the CA1 area. 4. 4. In addition to the reduction of functional inhibition, changes in excitatory neurotransmitter mechanisms were also found to contribute to the epileptiform burst discharge. A slow component of the epileptiform EPSP recorded from CA1 pyramidal cells has been recorded and was found to be antagonized by the NMDA-receptor antagonist D-APV. 5. 5. Methods of controlling epileptiform activity in the kainic acid lesioned hippocampus have been tested. Stimulation of the substantia nigra and ventral tegmental areas produced profound inhibition of pyramidal cell activity in control hippocampi; however, they were found to be ineffective in controlling the epileptiform burst. 6. 6. A second method involved the use of hippocampal suspension grafts. Whilst this approach has yielded some encouraging data, further studies are necessary before the mechanism of the improvement in inhibitory synaptic function can be explained.