GABAA

Cortical seizure mechanisms: insights from calcium, glutamate and GABA imaging

Focal neocortical epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood, but is likely to relate to the intermittent collapse of feed-forward GABAergic inhibition. Inhibition could fail through multiple mechanisms, including (i) an attenuation or even reversal of the driving force for chloride in postsynaptic neurons because of intense activation of GABAA receptors, (ii) an elevation of potassium secondary to chloride influx leading to depolarization of neurons, or (iii) insufficient GABA release from interneurons. I shall describe the results of experiments using fluorescence imaging of calcium, glutamate or GABA in awake rodent models of neocortical epileptiform activity. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagatedcentrifugally. GABA transients lasted longer than glutamate transients and were maximal ~1.5 mm from the focus. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing runaway recruitment of excitatory neurons as a fundamental mechanism underlying the escape of seizures from local inhibitory restraint.

PET imaging in brain diseases

Talk 1. PET based biomarkers of treatment efficacy in temporal lobe epilepsy A critical aspect of drug development involves identifying robust biomarkers of treatment response for use as surrogate endpoints in clinical trials. However, these biomarkers also have the capacity to inform mechanisms of disease pathogenesis and therapeutic efficacy. In this webinar, Dr Bianca Jupp will report on a series of studies using the GABAA PET ligand, [18F]-Flumazenil, to establish biomarkers of treatment response to a novel therapeutic for temporal lobe epilepsy, identifying affinity at this receptor as a key predictor of treatment outcome. Dr Bianca Jupp is a Research Fellow in the Department of Neuroscience, Monash University and Lead PET/CT Scientist at the Alfred Research Alliance–Monash Biomedical Imaging facility. Her research focuses on neuroimaging and its capacity to inform the neurobiology underlying neurological and neuropsychiatric disorders. Talk 2. The development of a PET radiotracer for reparative microglia Imaging of neuroinflammation is currently hindered by the technical limitations associated with TSPO imaging. In this webinar, Dr Lucy Vivash will discuss the development of PET radiotracers that specifically image reparative microglia through targeting the receptor kinase MerTK. This includes medicinal chemistry design and testing, radiochemistry, and in vitro and in vivo testing of lead tracers. Dr Lucy Vivash is a Research Fellow in the Department of Neuroscience, Monash University. Her research focuses on the preclinical development and clinical translation of novel PET radiotracers for the imaging of neurodegenerative diseases.

Synchrony and Synaptic Signaling in Cerebellar Circuits

The cerebellum permits a wide range of behaviors that involve sensorimotor integration. We have been investigating how specific cellular and synaptic specializations of cerebellar neurons measured in vitro, give rise to circuit activity in vivo. We have investigated these issues by studying Purkinje neurons as well as the large neurons of the mouse cerebellar nuclei, which form the major excitatory premotor projection from the cerebellum. Large CbN cells have ion channels that favor spontaneous action potential firing and GABAA receptors that generate ultra-fast inhibitory synaptic currents, raising the possibility that these biophysical attributes may permit CbN cells to respond differently to the degree of temporal coherence of their Purkinje cell inputs. In vivo, self-initiated motor programs associated with whisking correlates with asynchronous changes in Purkinje cell simple spiking that are asynchronous across the population. The resulting inhibition converges with mossy fiber excitation to yield little change in CbN cell firing, such that cerebellar output is low or cancelled. In contrast, externally applied sensory stimuli elicits a transient, synchronous inhibition of Purkinje cell simple spiking. During the resulting strong disinhibition of CbN cells, sensory-induced excitation from mossy fibers effectively drives cerebellar outputs that increase the magnitude of reflexive whisking. Purkinje cell synchrony, therefore, may be a key variable contributing to the “positive effort” hypothesized by David Marr in 1969 to be necessary for cerebellar control of movement.

Plasticity in hypothalamic circuits for oxytocin release

Mammalian babies are “sensory traps” for parents. Various sensory cues from the newborn are tremendously efficient in triggering parental responses in caregivers. We recently showed that core aspects of maternal behavior such as pup retrieval in response to infant vocalizations rely on active learning of auditory cues from pups facilitated by the neurohormone oxytocin (OT). Release of OT from the hypothalamus might thus help induce recognition of different infant cues but it is unknown what sensory stimuli can activate OT neurons. I performed unprecedented in vivo whole-cell and cell-attached recordings from optically-identified OT neurons in awake dams. I found that OT neurons, but not other hypothalamic cells, increased their firing rate after playback of pup distress vocalizations. Using anatomical tracing approaches and channelrhodopsin-assisted circuit mapping, I identified the projections and brain areas (including inferior colliculus, auditory cortex, and posterior intralaminar thalamus) relaying auditory information about social sounds to OT neurons. In hypothalamic brain slices, when optogenetically stimulating thalamic afferences to mimic high-frequency thalamic discharge, observed in vivo during pup calls playback, I found that thalamic activity led to long-term depression of synaptic inhibition in OT neurons. This was mediated by postsynaptic NMDARs-induced internalization of GABAARs. Therefore, persistent activation of OT neurons following pup calls in vivo is likely mediated by disinhibition. This gain modulation of OT neurons by infant cries, may be important for sustaining motivation. Using a genetically-encoded OT sensor, I demonstrated that pup calls were efficient in triggering OT release in downstream motivational areas. When thalamus projections to hypothalamus were inhibited with chemogenetics, dams exhibited longer latencies to retrieve crying pups, suggesting that the thalamus-hypothalamus noncanonical auditory pathway may be a specific circuit for the detection of social sounds, important for disinhibiting OT neurons, gating OT release in downstream brain areas, and speeding up maternal behavior.

a5-containing nicotinic acetylcholine receptor regulation of fast GABAa-mediated inhibition during Up and Down states

Comparing the efficacy of selective negative allosteric modulators of α5‐containing GABAA receptors on synaptic inhibition and cognitive deficits in a mouse model of Down syndrome

A conserved region at the end of the N-terminal extracellular domain of GABAA receptor subunits is crucial for the receptor forward trafficking

Cooperative effect of GABA and Ca2+ for the diffusion and trapping of GABAARs at synapses: regulation of receptor number

Differential modulation of GABAA and glycine receptors by Gelsemium alkaloids

Downregulation of extra-synaptic delta GABAA receptors is correlated with disrupted tonic inhibition in an APP knock-in mouse model of Alzheimer’s disease

Golexanolone, a GABAA receptor modulating steroid antagonist, reverses neuroinflammation in cerebellum and hippocampus and restores motor coordination and cognitive function in hyperammonemic rats

Modulation by neurosteroids of the GABAA receptors and Kir channels expressed in oligodendroglia

Pharmacology and desensitization properties of α4-containg GABAA receptors

Single molecule characterisation of α3-containing GABAARs reveals a unique role at inhibitory synapses

GABAA receptors modulate anxiety-like behavior through the central amygdala area in rats with higher physical activity

FENS Forum 2024

GABAA receptors and neuroligin 2 synergize to promote synaptic adhesion and inhibitory synaptogenesis

FENS Forum 2024

Golexanolone, a GABAA receptor-modulating steroid antagonist, improves neuroinflammation, fatigue, anxiety, depression, and some cognitive and motor alterations in a rat model of Parkinson's disease

FENS Forum 2024

An innovative strategy to identify new chemical classes of GABAA α5 receptor modulators

FENS Forum 2024