Inhibition Flashcards
(18 cards)
• Buhl et al (1994):
Dual intracellular recording from GABAergic interneurons in the hippocampus combining with EM analysis of synaptic connections ad 3 types of GABAergic cells and found they terminate at different locations of the principal neurons such that axo-axonic on AIS mainly, basket on soma or proximal dendrites and bistratified on dendrites. This with their difference in kinetics of the post-synaptic effects indicate different functions
• Lee et al (2010):
Whole cell patch clamp recordings in cerebellar mice granule cells to measure Cl- currents associated with tonic inhibition and found that tonic inhibition is due to GABA released by glia cells via Best1. Best1 knock down resulted in attenuation in the tonic current→ selective expression of Best 1 in glia cells rescoes tonic inhibition. Then expressing Best1 in HEK cells and whole cell patch clamping found that GABA permeates and is detected by second HEK cells expressing GABAC receptor
• Yoon et al (2014):
Found that gene silencing or KO of MAOB resulted in elimination of tonic GABA current in granule cells and MSNs or the cerebellum and striatum of mice and glia specific recue of MAOB rescues recovers the tonic inhibition.
• Marvin et al (2019):
Created iGABASnFR, a genetically encoded receptor that can detect GABA release evoked by electric stimulation of afferent fibres in acute brain slices and readily detectable fluorescent increases in vivo (e.g. in mice and zebrafish) and in vitro e.g. used in zebra fish to correlate GABAergic signalling across the cerebellum to motor output e.g. peaked roughly 20μs after swimming onset so reliably detect local GABA
o However not a ratiometric dye so can estimate the precise concentration
o More sensitive indicators required to separate phasic and tonic signalling
• Christensen et al (2014):
Used HEK cells and stably expressed GABAA receptors and recorded in vitro in turtles with whole cell patch clamp techniques. Found that measure ambient extrasynaptic GABA concentrations iat high spatial and temporal resolution so indicates can measure extrasynaptic GABA ad spill over
o Not yet used in vivo
Miles et al (1996)
Examined perisomatic and dendritic inhibition by recording from CA3 inhibitory and pyramidal cells in guinea pig brain slices and found that perisomatic inhibitory cells initiated the majority of simultaneous IPSPs seen in nearby Na+ AP whereas activation of dendritic could suppress Ca2+ dependant spikes suggesting that distinct inhibitory cells may differentially control dendritic electrogenesis and axonal output of hippocampal pyramidal cells. IPSPs were sufficient to veto spike generation Differential modulation of activity in subsets of inhibitory cells may provide a way to switch between different operational states of the hippocampal network
• Rudolph et al (1999):
): KI mutation of α1 into the GABAAR in germline mice and tested on elevated plus maze and rotarod and mice failed to show the sedative effect, amnesiac and partly the anticonvulsant actions of diazepam whereas anxiolytic effects were fully retained suggesting α1 has sedative property
• Engin et al (2014):
: KI mutation of α2 in GABAARs using a two-bottle choice drinking paradigm to evaluate midazolam preference and intracranial self-stimulation and found that they did not show midazolam-induced reward enhancement in ICSS compared to wt indicating that α2 may be responsible for the reward-related properties of benzodiazepine which may underlie repeated drug taking actions
• Low et al (2000).
Point mutation in α2 and α3 in GABAA and assessed anxiety e.g. with elevated plus maze and found that anxiolytic action of diazepam was absent in α2 KI but not α3 but still showed sedative and motor impairment effects. Could be potential treatment for anxiety
• Mitchell et al (2003):
dynamic clamp with whole cell patch clamp recordings in cerebellular granule cells, along with computational modelling to show that tonic inhibition reduces the gain and shifts the offset of cerebellar granule cell input-output relationships during frequency dependant excitation with synaptic conductance waveforms. Thus shunting inhibition scales the subthreshold voltage and acts as a gain control with minimal effects on the precise information encoded in fast excitatory effects
• Olah et al (2009):
Showed that neurogliaform cells release enough GABA for volume transmission within the axonal cloud enough not to require synapses to produce inhibitory responses and show that GABAAδ receptors are localised to neurogliaform cells preferentially among cortical interneuron and reach these receptors that are responsible for tonic inhibition. So show output of neurosteroid sensitive neuroglia cells represent the form of the lack of spatial specificity in GABA-mediated systems, leading to long lasting network hyperpolarisation combined with widespread suppression of communication in a local circuit
• Woo et al (2018):
Found reduction of tonic GABA release by genetic or pharmacological removal of Best1 and MAOB caused enhanced neuronal excitability, synaptic transmission and motor performance on rotarod test, whereas augmentation o tonic GABA release by astrocyte specific overexpression of MAOB caused opposite result. Suggest that actions of astrocyte GABA in excitation/inhibition and motor coordination. Reducing tonic inhibition seems to have beneficial effects as maybe a safety net overinhibited to prevent likelihood of going into seizure like activity
• Maguire et al (2005):
Using western blot analysis on membrane fractions from hippocampi of mice in estrus and late diestrus and found periodic alterations in specific GABAAR during the estrus cycle with late diestrus associated with enhanced δGABAAR expression increasing tonic inhibition and reflects diminished seizure susceptibility and anxiety. Eliminating cycling of δGABAARs by antisense RNA treatment or KO prevents lowering of excitability during diestrus
o Other effects during diestrus?
• Maldonado-Aviles et al (2009):
sed in situ hybridisation in prefrontal cortex od postmortem brains of schizophrenics and subjects and found levels of δ mRNA were significantly lower in patients with schizophrenia indicating abnormalities in tonic inhibition could play a role in schizophrenia
o Cause or consequence
• Mariotti et al (2018):
Whole cell current clamp recordings of SOM interneurons in somatosensory cortex and Ca2+ imaging of astrocytes (loading with Flu-4AM). Using optogenetics and 2 photon imaging found that SOM expressing interneurons produce robust GABABR mediated elevations in the astrocytes, repetitive stimulation sof the SOM interneurons → potentiation. The potentiated response depended on SOM as was prevented with antagonists. This suggests that signalling specificity between interneuron subtype and astrocytes provide a new perspective in the role of astrocytes as non neuronal components of inhibitory circutis
• Gulledge and Stuart (2003):
Using extracellular and gramicidin perforated patch recordings showed that somatic and dendritic GABA responses in mature cortical pyramidal neurons are depolarising from rest and can facilitate AP generation when combined with proximal excitatory input. Found that dendritic GABA always excitatory but somatic could be inhibitory if GABA input was coincident with excitatory input. Suggest play a role in synaptic integration
• Vida et al (2006):
Used gramicidin-perforated patch clamp recordings to measure the GABAA-mediated inhibition of basket cells and found these mature interneurons of hippocampal dentate gyrus is shunting rather than depolarising. When combining this into a structured interneuron network model, found that shunting inhibition increased the robustness of gamma oscillations in the brain compared to hyperpolarising inhibition
• Wilson and Nicoll (2001):
Recording CA1 pyramidal cells in rat hippocampal slices and showed that there was a suppression of GABA-mediated transmission following depolarisation of hippocampal pyramidal neurons which is mediated by retrograde signalling of endogenous cannabinoids, DSI was blocked by antagonists of CB1 receptors. CB1- expressing interneurons are thought to control hippocampal oscillations in theta and gamma frequency ad CB1 agonists decrease the power of synchronous oscillations in hippocampal slices suggesting retrograde endocannabinoid signalling may decrease the power of synchronous spiking of hippocampal cells.
o Don’t actually look to see if mediated by GABA interneurons
