Muscarinic Receptor Loss and Preservation of Presynaptic Cholinergic Terminals in Hippocampal Sclerosis

Pennell, Page B.; Burdette, David E.; Ross, Donald A.; Henry, Thomas R.; Albin, Roger L.; Sackellares, J. Chris; Frey, K.A.

doi:10.1111/j.1528-1157.1999.tb01986.x

Cited by 15 publications

(9 citation statements)

References 56 publications

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“…No reduction but rather a slight trend toward increased VAChT binding sites was observed when compared to autopsy controls, as opposed to a significant reduction in mAChRs. This indicates the relative preservation of the cholinergic projecting terminals that is consistent with an axon sparing lesion as opposed to neuronal cell loss in the process of hippocampal sclerosis (Pennell et al, 1999). An explanation for the slight increase in VAChT binding sites may be due to a relative concentration of septohippocampal presynaptic terminals due to synaptic reorganization in the setting of hippocampal atrophy.…”

Section: Slc18 Familymentioning

confidence: 80%

Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

Liefferinge¹,

Massie²,

Portelli³

et al. 2013

Front. Cell. Neurosci.

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The vesicular neurotransmitter transporters (VNTs) are small proteins responsible for packing synaptic vesicles with neurotransmitters thereby determining the amount of neurotransmitter released per vesicle through fusion in both neurons and glial cells. Each transporter subtype was classically seen as a specific neuronal marker of the respective nerve cells containing that particular neurotransmitter or structurally related neurotransmitters. More recently, however, it has become apparent that common neurotransmitters can also act as co-transmitters, adding complexity to neurotransmitter release and suggesting intriguing roles for VNTs therein. We will first describe the current knowledge on vesicular glutamate transporters (VGLUT1/2/3), the vesicular excitatory amino acid transporter (VEAT), the vesicular nucleotide transporter (VNUT), vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT) and the vesicular γ-aminobutyric acid (GABA) transporter (VGAT) in the brain. We will focus on evidence regarding transgenic mice with disruptions in VNTs in different models of seizures and epilepsy. We will also describe the known alterations and reorganizations in the expression levels of these VNTs in rodent models for temporal lobe epilepsy (TLE) and in human tissue resected for epilepsy surgery. Finally, we will discuss perspectives on opportunities and challenges for VNTs as targets for possible future epilepsy therapies.

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Section: Slc18 Familymentioning

confidence: 80%

Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

Liefferinge¹,

Massie²,

Portelli³

et al. 2013

Front. Cell. Neurosci.

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“…In support of this idea, septal atrophy occurs following hippocampal excitotoxic ablation 21 or septo-hippocampal disconnection. 19 In the context of these prior animal studies, as well as studies of human tissue obtained at temporal lobectomy indicating increased septal cholinergic innervation of hippocampus in TLE, [22][23][24] we suggest our finding of septal enlargement in human TLE without MTS represents MRI-detectable evidence of neuroplasticity/augmentation of the septal-hippocampal system in TLE.…”

Section: 2mentioning

confidence: 98%

Septal nuclei enlargement in human temporal lobe epilepsy without mesial temporal sclerosis

Butler

Záborszky²,

Wang³

et al. 2013

Neurology

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Objective: To measure the volume of basal forebrain septal nuclei in patients with temporal lobe epilepsy (TLE) as compared to patients with extratemporal epilepsy and controls. In animal models of TLE, septal lesions facilitate epileptogenesis, while septal stimulation is antiepileptic.Method: Subjects were recruited from 2 sites and consisted of patients with pharmacoresistant focal epilepsy (20 with TLE and mesial temporal sclerosis [MTS], 24 with TLE without MTS, 23 with extratemporal epilepsy) and 114 controls. Septal volume was measured using high-resolution MRI in association with newly developed probabilistic septal nuclei maps. Septal volume was compared between subject groups while controlling for relevant factors.Results: Patients with TLE without MTS had significantly larger septal nuclei than patients with extratemporal epilepsy and controls. This was not true for patients with MTS. These results are interpreted with reference to prior studies demonstrating expansion of the septo-hippocampal cholinergic system in animal models of TLE and human TLE surgical specimens. Human septal nuclei, located in the basal forebrain, consist of the medial septum and diagonal band of Broca. Septal nuclei provide the main cholinergic input to the hippocampus via the fimbria/fornix 1 and are critical for hippocampal theta oscillations that mediate learning and memory. 2,3 In animal models of temporal lobe epilepsy (TLE), medial septal lesions facilitate epileptogenesis, and chemical or electrical septal stimulation can stop and prevent seizures. Conclusion:4-8 To our knowledge, no studies have examined septal nuclei structure in human TLE.We used MRI in association with probabilistic maps of human septal nuclei 9 to measure septal volume in patients with TLE either with or without mesial temporal sclerosis (MTS), patients with partial epilepsy not involving the hippocampus (extratemporal epilepsy [ETE]), and healthy controls. Based on prior human MRI studies showing atrophy of hippocampi and connected limbic regions in TLE including the fornix, 10,11 we initially hypothesized that septal volume would be reduced in TLE. Contrary to this hypothesis, we found septal enlargement in TLE without MTS.METHODS Subjects. All subjects provided informed consent to participate in this institutional review board-approved study. Patients with epilepsy were recruited from either the New York University (NYU) or University of California, San Diego (UCSD) Epilepsy Center. See table 1 for subject information. All patients had medically intractable seizures and were being considered for epilepsy surgery. Seizure focus lateralization/localization was made by experienced epileptologists based on clinical criteria including neuroimaging, video-EEG, and intracranial EEG (icEEG) when available. Patients with TLE were categorized as having MTS (TLE-MTS) or not based on standard criteria.12 PatientsFrom the Comprehensive Epilepsy Center (T.B., X

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“…However, it has been established that there are characteristic patterns of neuronal loss and dendritic damage associated with alterations in neurotransmitter receptor densities in the epileptogenic hippocampus. 19,20,21,22,23,24 The traditional interpretation of these findings is that the epileptogenic hippocampus generates seizures due to a loss of inhibition or an excess of excitation. However, it is our contention that these static changes in neuronal circuitry cannot account for the intermittency of seizures, unless one considers the dynamical impact of these anatomical and biochemical changes.…”

Section: Introductionmentioning

confidence: 99%

Epilepsy – When Chaos Fails

et al. 2000

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Temporal lobe epilepsy is characterized by episodic paroxysmal electrical discharges (ictal activity) originating in mesial structures of the temporal lobe. These discharges consist of organized synchronous activity of mesial temporal neurons, particularly those of the hippocampus. This activity is seen as rhythmic medium to high amplitude slow waves or spike and slow wave discharges on the electroencephalogram (EEG). The ictal discharges (seizures) often spread to involve widespread regions of the ipsilateral then the contralateral cerebral hemispheres. These diffuse discharges often persist for approximately 1 to 5 minutes and are followed by a postictal pattern of asynchronous low amplitude slow waves in the EEG. It is a widely held view that seizures arise from mesial temporal structures because of damage to hippocampal circuitry. The characteristic circuit abnormalities include drop out of neurons, simplification of the dendritic tree (reduced synaptic input), sprouting of dentate granule cell axons (increasing the number of excitatory-excitatory feedback connections), and increase in glial cell elements (sclerosis). There is a concomitant loss in neurotransmitter receptors in the hippocampus. Physiologic studies in epileptogenic hippocampi have demonstrated loss of neuronal inhibition. It is generally believed that loss of inhibition is, at least in part, responsible for the occurrence of epileptic seizures. The central questions as to why seizures occur intermittently, and begin and end when they do, remain unanswered. The structural abnormalities of the temporal lobe are relatively stable, yet they exhibit dramatically variable behavior, as characterized by the EEG. For example, during the interictal state, the EEG pattern is described by electroencephalographers as low to medium voltage, "irregular" and "arrhythmic". This contrasts with the "organized", "rhythmic", and self-sustained characteristics of ictal EEG pattern. We have postulated that epileptic brains, being chaotic nonlinear systems, repeatedly make the abrupt transitions into and out of the ictal state because the epileptogenic focus drives them into selforganizing phase transitions from chaos to order. Further, we postulated that the seizure serves to reset the system. Our hypotheses have been supported by the following findings: (1) positive In: Chaos in the brain? Eds. K. Lehnertz & C.E. Elger, World Scientific, Singapore, in press EpilepsyChaos2.doc submitted to World Scientific 01/03/00 : 2:16 PM 2 Lyapunov exponent in EEG signal (2) nonlinearities in interictal EEG generated by the epileptogenic focus, (3) existence of a spatiotemporal transition in EEG dynamics (from chaos to order) preceding seizures by minutes to hours to days and (4) resetting of spatiotemporal dynamics by the seizure (from order to chaos), leading to the more favorable interictal condition. These observations were made in scalp and intracranial EEG recordings from patients with epileptic seizures of frontal as well as mesial temporal origin. Thus, although an epile...

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Muscarinic Receptor Loss and Preservation of Presynaptic Cholinergic Terminals in Hippocampal Sclerosis

Cited by 15 publications

References 56 publications

Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

Septal nuclei enlargement in human temporal lobe epilepsy without mesial temporal sclerosis

Epilepsy – When Chaos Fails

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