Astrocyte control of synaptic NMDA receptors contributes to the progressive development of temporal lobe epilepsy

Abstract

Astrocytes modulate neuronal activity, synaptic transmission, and behavior by releasing chemical transmitters in a process termed gliotransmission. Whether this process impacts epilepsy in vivo is not known. We show that genetic impairment of transmitter release from astrocytes by the expression of a glial dominantnegative SNARE domain in mice reduced epileptiform activity in situ, delayed seizure onset after pilocarpine-induced status epilepticus, and attenuated subsequent progressive increase in seizure frequency in vivo. The reduced seizure frequency was accompanied by attenuation of hippocampal damage and behavioral deficits. As the delay in seizure onset and the reduced seizure frequency were mimicked by intracerebroventricular delivery of the NMDA receptor (NMDAR) antagonist D-(-)-2-amino-5-phosphonopentanoate in WT littermates and because dominant-negative SNARE expression leads to a hypofunction of synaptic NMDARs, we conclude that astrocytes modulate epileptogenesis, recurrent spontaneous seizures, and pathophysiological consequences of epilepsy through a pathway involving NMDARs.glia-to-neuron signaling | pilocarpine mouse | electroencephalography | hippocampus | interictal spikes T emporal lobe epilepsy (TLE), one of the most common neurological disorders, which affects 1% of the population worldwide, is characterized by the occurrence of recurring unprovoked spontaneous seizures. Unfortunately, seizures in 30% of patients with TLE are not controlled by anticonvulsant agents, drugs that are directed to neuronal targets. In this case, patients may undergo resective epilepsy surgery to become seizure-free (1).Emerging evidence suggests a critical role for the glial cells, astrocytes, in epilepsy (2, 3). Astrocytes play an important role in maintaining central nervous system function by releasing gliotransmitters, including glutamate, D-serine, and ATP (4). Whether gliotransmission contributes to epilepsy in vivo has not been established. It has recently been shown that gliotransmission regulates the trafficking and surface expression of the neuronal N-methyl-D-aspartate receptor (NMDAR) subunits 2A and 2B (5, 6). Because of the importance of NMDARs in epilepsy (7), we hypothesize that astrocytes modulate epileptic seizures by regulating these receptors. To test this hypothesis, we used astrocytespecific molecular genetics in mice to inhibit transmitter release from astrocytes, along with the in vivo pilocarpine model of TLE, long-term continuous video EEG, and an in situ hippocampal slice model of epilepsy.We show that genetic impairment of transmitter release from astrocytes by the expression of glial dominant-negative SNARE (dnSNARE) (8) delayed the onset of spontaneous recurrent seizures (SRSs) and attenuated the progressive increase in frequency of SRSs, hippocampal sclerosis, and the appearance of aberrant open-field behaviors. Similarly, chemically induced epileptiform activity in situ was attenuated by the expression of astrocytic dnSNARE. The ability of dnSNARE to reduce epileptiform activity in...

Characterization of Human Hippocampal Neural Stem/Progenitor Cells and Their Application to Physiologically Relevant Assays for Multiple Ionotropic Glutamate Receptors

“…Hippocampal sclerosis is commonly observed in patients with temporal lobe epilepsy (TLE). 12 Clasadonte et al 13 demonstrated in a mouse pilocarpine model of TLE that hyperfunction of NMDARs at the CA1 hippocampal synapses causes hippocampal sclerosis and that astrocytes play an important role in controlling NMDARs by releasing chemical transmitters in a process termed gliotransmission.…”

“…The hippocampus is an important brain region involved in neurological disorders such as AD, schizophrenia, and epilepsy. [10][11][12][13] Therefore, we need to develop an assay system that uses human hippocampal neurons so that we can obtain a detailed understanding of the molecular mechanisms underlying these diseases and discover novel drugs for treating them.…”

How Do Astrocytes Participate in Neural Plasticity?

“…In most of these studies, LTP was triggered by high-frequency stimulation (HFS), and the effects of genetic or pharmacological manipulation of astrocytes assessed in parallel. In the first study of astrocytes in LTP, dominant-negative inhibition of vesicular release (soluble NSF attachment protein receptors [SNARE]) under the astrocyte-specific promoter, glial fibrillary acidic protein (GFAP), lowered baseline adenosine concentration (Pascual et al 2005), which leads to a long-term change in postsynaptic NMDAR trafficking (Clasadonte et al 2013), and, as a consequence, leads to a change in modulation of the magnitude of NMDAR-dependent LTP. In another study, Dserine release from astrocytes was shown to be critical for NMDAR-dependent LTP (Henneberger et al 2010).…”

Maternal immune activation increases seizure susceptibility in juvenile rat offspring

“…In recent years, accumulating data have suggested that astrocyte dysfunction contributes to the development of epilepsy, including seizure occurrence, neuronal damage, and behavioral impairment [15][16][17]. Excessive or prolonged reactive astrogliosis is a recognized response to seizures and a potential contributor to mechanisms of epileptogenesis [18,19].…”