Growing evidence from rodent models of temporal lobe epilepsy (TLE) indicates that dysregulation of the mammalian target of rapamycin (mTOR) pathway is involved in seizures and epileptogenesis. However, the role of the mTOR pathway in the epileptogenic process remains poorly understood. Here, we used an animal model of TLE and sclerotic hippocampus from patients with refractory TLE to determine whether cell-type specific activation of mTOR signaling occurs during each stage of epileptogenesis. In the TLE mouse model, we found that hyperactivation of the mTOR pathway is present in distinct hippocampal subfields at three different stages after kainate-induced seizures, and occurs in neurons of the granular and pyramidal cell layers, in reactive astrocytes, and in dispersed granule cells, respectively. In agreement with the findings in TLE mice, upregulated mTOR was observed in the sclerotic hippocampus of TLE patients. All sclerotic hippocampus (n = 13) exhibited widespread reactive astrocytes with overactivated mTOR, some of which invaded the dispersed granular layer. Moreover, two sclerotic hippocampus exhibited mTOR activation in some of the granule cells, which was accompanied by cell body hypertrophy. Taken together, our results indicate that mTOR activation is most prominent in reactive astrocytes in both an animal model of TLE and the sclerotic hippocampus from patients with drug resistant TLE.
Sha et al. report that Hsp90β, which is up-regulated in astrocytes of human epileptogenic tissue, interacts with GLT-1 and recruits it to 20S proteasome for degradation. The Hsp90 inhibitor 17AAG exhibits beneficial effects in a model of temporal lobe epilepsy.
Notch signaling in the nervous system is often regarded as a developmental pathway. However, recent studies have suggested that Notch is associated with neuronal discharges. Here, focusing on temporal lobe epilepsy, we found that Notch signaling was activated in the kainic acid (KA)-induced epilepsy model and in human epileptogenic tissues. Using an acute model of seizures, we showed that DAPT, an inhibitor of Notch, inhibited ictal activity. In contrast, pretreatment with exogenous Jagged1 to elevate Notch signaling before KA application had proconvulsant effects. In vivo, we demonstrated that the impacts of activated Notch signaling on seizures can in part be attributed to the regulatory role of Notch signaling on excitatory synaptic activity in CA1 pyramidal neurons. In vitro, we found that DAPT treatment impaired synaptic vesicle endocytosis in cultured hippocampal neurons. Taken together, our findings suggest a correlation between aberrant Notch signaling and epileptic seizures. Notch signaling is up-regulated in response to seizure activity, and its activation further promotes neuronal excitation of CA1 pyramidal neurons in acute seizures.
Germline and somatic mutations in key genes of the mammalian target of rapamycin (mTOR) pathway have been identified in seizure-associated disorders. mTOR mutations lead to aberrant activation of mTOR signaling, and, although affected neurons are critical for epileptogenesis, the role of mTOR activation in glial cells remains poorly understood. We previously reported a consistent activation of the mTOR pathway in astrocytes in the epileptic foci of temporal lobe epilepsy. In this study, it was demonstrated that mTOR deletion from reactive astrocytes prevents increases in seizure frequency over the disease course. By using a tamoxifen-inducible mTOR conditional knockout system and kainic acid, a model was developed that allowed astrocyte-specific mTOR gene deletion in mice with chronic epilepsy. Animals in which mTOR was deleted from 44 % of the astrocyte population exhibited a lower seizure frequency compared with controls. Down-regulation of mTOR significantly ameliorated astrogliosis in the sclerotic hippocampus but did not rescue mossy fiber sprouting. In cultured astrocytes, the mTOR pathway modulated the stability of the astroglial glutamate transporter 1 (Glt1) and influenced the ability of astrocytes to remove extracellular glutamate. Taken together, these data indicate that astrocytes with activated mTOR signaling may provide conditions that are favorable for spontaneous recurrent seizures.
When it comes to mechanisms of brain functions such as learning and memory mediated by neural networks, existing multichannel electrophysiological detection and regulation technology at the cellular level does not suffice. To address this challenge, a 128-channel microelectrode array (MEA) was fabricated for electrical stimulation (ES) training and electrophysiological recording of the hippocampal neurons in vitro. The PEDOT:PSS/PtNPs-coated microelectrodes dramatically promote the recording and electrical stimulation performance. The MEA exhibited low impedance (10.94 ± 0.49 kohm), small phase delay (−12.54 ± 0.51°), high charge storage capacity (14.84 ± 2.72 mC/cm2), and high maximum safe injection charge density (4.37 ± 0.22 mC/cm2), meeting the specific requirements for training neural networks in vitro. A series of ESs at various frequencies was applied to the neuronal cultures in vitro, seeking the optimum training mode that enables the neuron to display the most obvious plasticity, and 1 Hz ES was determined. The network learning process, including three consecutive trainings, affected the original random spontaneous activity. Along with that, the firing pattern gradually changed to burst and the correlation and synchrony of the neuronal activity in the network have progressively improved, increasing by 314% and 240%, respectively. The neurons remembered these changes for at least 4 h. Collectively, ES activates the learning and memory functions of neurons, which is manifested in transformations in the discharge pattern and the improvement of network correlation and synchrony. This study offers a high-performance MEA revealing the underlying learning and memory functions of the brain and therefore serves as a useful tool for the development of brain functions in the future.
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