Trends in Neurosciences
ReviewA role for GABAB receptors in excitation and inhibition of thalamocortical cells
Abstract
Gamma-aminobutyric acid (GABA) in the thalamus has mainly been associated with the inhibitory modulation of the sensory and cortical flow of information via a ‘classical’, chloride-dependent, GABAA receptor-mediated action. However, the discovery of a late, long-lasting potassium-dependent inhibitory postsynaptic potential (IPSP) mediated by GABAB receptors present on thalamocortical cells, has allowed new insights into our understanding of the physiological role of this neurotransmitter. In particular, work on the dorsal lateral geniculate nucleus indicates that together with a relatively weak inhibition, GABAB receptor-mediated IPSPs ‘prepare’ thalamocortical cells for burst firing by activating low-threshold calcium potentials. Thus, GABA in the thalamus can no longer be viewed only as a ‘classical’ inhibitory transmitter but also as a neuromodulator with a ‘priming’ role for burst firing excitation. This dual role of GABAB receptors in inhibition and excitation of thalamocortical cells might allow different interpretations of earlier findings in animals and humans, both in healthy and pathological conditions. It will also help to identify new functions for postsynaptic GABAB receptors in other parts of the central nervous system.
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Increased propensity for infantile spasms and altered neocortical excitation-inhibition balance in a mouse model of down syndrome carrying human chromosome 21
2023, Neurobiology of DiseaseChildren with Down syndrome (DS, trisomy of chromosome 21) have an increased risk of infantile spasms (IS). As an epileptic encephalopathy, IS may further impair cognitive function and exacerbate neurodevelopmental delays already present in children with DS. To investigate the pathophysiology of IS in DS, we induced IS-like epileptic spasms in a genetic mouse model of DS that carries human chromosome 21q, TcMAC21, the animal model most closely representing gene dosage imbalance in DS. Repetitive extensor/flexor spasms were induced by the GABAB receptor agonist γ-butyrolactone (GBL) and occurred predominantly in young TcMAC21 mice (85%) but also in some euploid mice (25%). During GBL application, background electroencephalographic (EEG) amplitude was reduced, and rhythmic, sharp-and-slow wave activity or high-amplitude burst (epileptiform) events emerged in both TcMAC21 and euploid mice. Spasms occurred only during EEG bursts, but not every burst was accompanied by a spasm. Electrophysiological experiments revealed that basic membrane properties (resting membrane potential, input resistance, action-potential threshold and amplitude, rheobase, input-output relationship) of layer V pyramidal neurons were not different between TcMAC21 mice and euploid controls. However, excitatory postsynaptic currents (EPSCs) evoked at various intensities were significantly larger in TcMAC21 mice than euploid controls, while inhibitory postsynaptic currents (IPSCs) were similar between the two groups, resulting in an increased excitation-inhibition (E-I) ratio. These data show that behavioral spasms with epileptic EEG activity can be induced in young TcMAC21 DS mice, providing proof-of-concept evidence for increased IS susceptibility in these DS mice. Our findings also show that basic membrane properties are similar in TcMAC21 and euploid mice, while the neocortical E-I balance is altered to favor increased excitation in TcMAC21 mice, which may predispose to IS generation.
The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities
2022, IBRO Neuroscience ReportsThis review discusses the long-term effects of early-life environment on epileptogenesis, epilepsy, and neuropsychiatric comorbidities with an emphasis on the absence epilepsy. The WAG/Rij rat strain is a well-validated genetic model of absence epilepsy with mild depression-like (dysthymia) comorbidity. Although pathologic phenotype in WAG/Rij rats is genetically determined, convincing evidence presented in this review suggests that the absence epilepsy and depression-like comorbidity in WAG/Rij rats may be governed by early-life events, such as prenatal drug exposure, early-life stress, neonatal maternal separation, neonatal handling, maternal care, environmental enrichment, neonatal sensory impairments, neonatal tactile stimulation, and maternal diet. The data, as presented here, indicate that some early environmental events can promote and accelerate the development of absence seizures and their neuropsychiatric comorbidities, while others may exert anti-epileptogenic and disease-modifying effects. The early environment can lead to phenotypic alterations in offspring due to epigenetic modifications of gene expression, which may have maladaptive consequences or represent a therapeutic value. Targeting DNA methylation with a maternal methyl-enriched diet during the perinatal period appears to be a new preventive epigenetic anti-absence therapy. A number of caveats related to the maternal methyl-enriched diet and prospects for future research are discussed.
Testing broad-spectrum and isoform-preferring HCN channel blockers for anticonvulsant properties in mice
2020, Epilepsy ResearchHyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been implicated in the pathogenesis of epilepsy and consequently as targets for anticonvulsant drugs. Consistent with this, broad-spectrum block of HCN-mediated current (Ih) reduces seizure susceptibility in a variety of epilepsy models. However, HCN channel isoforms have distinct biophysical characteristics and anatomical expression suggesting that they may play different roles in setting neuronal excitability. Here we confirm that the broad-spectrum blocker ivabradine is effective at reducing seizure susceptibility in the s.c.PTZ seizure assay and extend this, showing efficacy of this drug in a thermogenic assay that models febrile seizures. Ivabradine is also effective at reducing thermogenic seizures in the Scn1a mouse model of Dravet syndrome in which febrile seizures are a feature. HCN isoform-preferring drugs were tested in the s.c.PTZ seizure assay. We confirm that the HCN4-preferring drug, EC18, is efficacious in reducing seizure susceptibility. Conversely, the HCN2/1-preferring drug, MEL55A, increased seizure susceptibility in the s.c.PTZ seizure assay. MEL57A, an HCN1-preferring drug, had no effect on seizure susceptibility. Mouse pharmacokinetic studies (for MEL55A and MEL57A) and screening against additional ion channels have not been thoroughly investigated on the HCN isoform-preferring compounds. Our results need to be considered in this light. Nevertheless, these data suggest that HCN isoform-selective block can have a differential impact on seizure susceptibility. This motivates the need to develop more HCN isoform-selective compounds to better explore this idea.
GABA receptors and T-type Ca<sup>2+</sup> channels crosstalk in thalamic networks
2018, NeuropharmacologyAlthough the thalamus presents a rather limited repertoire of GABAergic cell types compare to other CNS area, this structure is a privileged system to study how GABA impacts neuronal network excitability. Indeed both glutamatergic thalamocortical (TC) and GABAergic nucleus reticularis thalami (NRT) neurons present a high expression of T-type voltage-dependent Ca2+ channels whose activation that shapes the output of the thalamus critically depends upon a preceding hyperpolarisation. Because of this strict dependence, a tight functional link between GABA mediated hyperpolarization and T-currents characterizes the thalamic network excitability. In this review we summarize a number of studies showing that the relationships between the various thalamic GABAA/B receptors and T-channels are complex and bidirectional. We discuss how this dynamic interaction sets the global intrathalamic network activity and its long-term plasticity and highlight how the functional relationship between GABA release and T-channel-dependent excitability is finely tuned by the T-channel activation itself. Finally, we illustrate how an impaired balance between T-channels and GABA receptors can lead to pathologically abnormal cellular and network behaviours.
This article is part of the “Special Issue Dedicated to Norman G. Bowery”.
Comparing glutamatergic neuron population in the mediodorsal thalamic nucleus of genetic absence epilepsy rats from strasbourg (GAERS) and normal control Wistar rats
2016, Journal of Chemical NeuroanatomyAn imbalance between GABAergic inhibition and glutamatergic excitation is suspected to play a role in the genesis of epileptic processes. In the present study we quantified the number of glutamate+ve neurons in the mediodorsal thalamic nucleus (MD) of genetic absence epilepsy rats from Strasbourg (GAERS) and compared these with values for normal Wistar rats.
The MD thalamic nucleus was removed from each animal and the glutamatergic neurons were labelled using light-microscopy glutamate immunohistochemistry. The disector method was used to quantify the glutamate+ve neurons in the MD thalamic nucleus of GAERS and Wistar rats. The data were statistically analyzed.
In the Wistar animals glutamate+ve neurons formed 89% and in GAERS 92.3% of the total neurons in 1000 μm3 of MD thalamic nucleus. In GAERS glutamate+ve neurons showed statistically significant increase in the MD thalamic nucleus compared to Wistar animals. In Wistar animals the glutamate−ve neurons formed 11% and in GAERS 7.7% of the total neurons in 1000 μm3 of MD thalamic. No significant difference was observed in glutamate−ve neurons between the two strains. The average diameter of glutamate+ve neurons showed no significance, while glutamate−ve neurons were significant between the two strains.
The results of the present study, on genetic absence epilepsy model, GAERS, confirms the role of MD thalamic nucleus in chemically induced absence epilepsy.
The mediodorsal thalamus as a higher order thalamic relay nucleus important for learning and decision-making
2015, Neuroscience and Biobehavioral ReviewsRecent evidence from monkey models of cognition shows that the magnocellular subdivision of the mediodorsal thalamus (MDmc) is more critical for learning new information than for retention of previously acquired information. Further, consistent evidence in animal models shows the mediodorsal thalamus (MD) contributes to adaptive decision-making. It is assumed that prefrontal cortex (PFC) and medial temporal lobes govern these cognitive processes so this evidence suggests that MD contributes a role in these cognitive processes too. Anatomically, the MD has extensive excitatory cortico-thalamo-cortical connections, especially with the PFC. MD also receives modulatory inputs from forebrain, midbrain and brainstem regions. It is suggested that the MD is a higher order thalamic relay of the PFC due to the dual cortico-thalamic inputs from layer V (‘driver’ inputs capable of transmitting a message) and layer VI (‘modulator’ inputs) of the PFC. Thus, the MD thalamic relay may support the transfer of information across the PFC via this indirect thalamic route. This review summarizes the current knowledge about the anatomy of MD as a higher order thalamic relay. It also reviews behavioral and electrophysiological studies in animals to consider how MD might support the transfer of information across the cortex during learning and decision-making. Current evidence suggests the MD is particularly important during rapid trial-by-trial associative learning and decision-making paradigms that involve multiple cognitive processes. Further studies need to consider the influence of the MD higher order relay to advance our knowledge about how the cortex processes higher order cognition.