Synaptic changes in GABAA receptor expression in the thalamus of the stargazer mouse model of absence epilepsy

Seo, Steve; Leitch, Beulah

doi:10.1016/j.neuroscience.2015.08.021

Cited by 23 publications

(10 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ensuing diminished feed-forward inhibition of VP may lead to hyperexcited VP neurons, which can result in enhanced feedback inhibition onto VP neurons, following the thalamocortical recruitment of RTN neurons. The secondary changes observed in stargazers, in particular enhanced tonic inhibition 71 , and increased expression of GABAR subunits in VP 72 73 , are compatible with this model, as these may be compensatory mechanisms to overcome the weakened feed-forward inhibitory input.…”

Section: Discussionsupporting

confidence: 57%

See 1 more Smart Citation

NMDA Receptor Expression in the Thalamus of the Stargazer Model of Absence Epilepsy

Barad

Grattan

Leitch

2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

In the stargazer mouse model of absence epilepsy, altered corticothalamic excitation of reticular thalamic nucleus (RTN) neurons has been suggested to contribute to abnormal synchronicity in the corticothalamic-thalamocortical circuit, leading to spike-wave discharges, the hallmark of absence seizures. AMPA receptor expression and function are decreased in stargazer RTN, due to a mutation of AMPAR auxiliary subunit stargazin. It is unresolved and debated, however, if decreased excitation of RTN is compatible with epileptogenesis. We tested the hypothesis that relative NMDAR expression may be increased in RTN and/or thalamic synapses in stargazers using Western blot on dissected thalamic nuclei and biochemically isolated synapses, as well as immunogold cytochemistry in RTN. Expression of main NMDAR subunits was variable in stargazer RTN and relay thalamus; however, mean expression values were not statistically significantly different compared to controls. Furthermore, no systematic changes in synaptic NMDAR levels could be detected in stargazer thalamus. In contrast, AMPAR subunits were markedly decreased in both nucleus-specific and synaptic preparations. Thus, defective AMPAR trafficking in stargazer thalamus does not appear to lead to a ubiquitous compensatory increase in total and synaptic NMDAR expression, suggesting that elevated NMDAR function is not mediated by changes in protein expression in stargazer mice.

show abstract

Section: Discussionsupporting

confidence: 57%

“…Tissue processing and EM immunocytochemistry were performed following previously established methods 25 73 77 . Adult male stargazer and control mice from three separate litters were terminally anesthetized, and transcardially perfused with 4% paraformaldehyde-0.1% glutaraldehyde in 0.1 M PB, pH7.4.…”

Section: Methodsmentioning

confidence: 99%

NMDA Receptor Expression in the Thalamus of the Stargazer Model of Absence Epilepsy

Barad

Grattan

Leitch

2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…The monoclonal antibody against gephyrin raised in mouse was previously used to identify GABAergic synapses using array tomography 32 . The rabbit anti-GABA A α1 receptor antisera have been used for both fluorescence microscopy and for post-embedding immunogold labeling in electron microscopy 34,35 . microscopy and image processing.…”

Section: Stereotactic Injectionsmentioning

confidence: 99%

Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse

Meye¹,

Soiza-Reilly²,

Smit³

et al. 2016

Nat Neurosci

130

151

View full text Add to dashboard Cite

Cocaine withdrawal produces aversive states and vulnerability to relapse, hallmarks of addiction. The lateral habenula (LHb) encodes negative stimuli and contributes to aversive withdrawal symptoms. However, it remains unclear which inputs to LHb promote this and what the consequences are for relapse susceptibility. We report, using rabies-based retrolabeling and optogenetic mapping, that the entopeduncular nucleus (EPN, the mouse equivalent of the globus pallidus interna) projects to an LHb neuronal subset innervating aversion-encoding midbrain GABA neurons. EPN-to-LHb excitatory signaling is limited by GABAergic cotransmission. This inhibitory component decreases during cocaine withdrawal as a result of reduced presynaptic vesicular GABA transporter (VGAT). This shifts the EPN-to-LHb GABA/glutamate balance, disinhibiting EPN-driven LHb activity. Selective virally mediated VGAT overexpression at EPN-to-LHb terminals during withdrawal normalizes GABAergic neurotransmission. This intervention rescues cocaine-evoked aversive states and prevents stress-induced reinstatement, used to model relapse. This identifies diminished inhibitory transmission at EPN-to-LHb GABA/glutamate synapses as a mechanism contributing to the relapsing feature of addictive behavior.

show abstract

“…Tissue samples were processed and analyzed according to previously established protocols from our group ( Barad et al, 2012 ; Shevtsova and Leitch, 2012 ; Seo and Leitch, 2015 ). Mice were anesthetized with sodium pentobarbital (60 mg/kg, Pentobarb 300), and then sacrificed by transcardial perfusion with 4% paraformaldehyde and 0.1% glutaraldehyde in 0.1 M Sorensen’s phosphate buffer (PB).…”

Section: Methodsmentioning

confidence: 99%

Synaptic Changes in AMPA Receptor Subunit Expression in Cortical Parvalbumin Interneurons in the Stargazer Model of Absence Epilepsy

Adotevi

Leitch

2017

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Feedforward inhibition is essential to prevent run away excitation within the brain. Recent evidence suggests that a loss of feed-forward inhibition in the corticothalamocortical circuitry may underlie some absence seizures. However, it is unclear if this aberration is specifically linked to loss of synaptic excitation onto local fast-spiking parvalbumin-containing (PV+) inhibitory interneurons, which are responsible for mediating feedforward inhibition within cortical networks. We recently reported a global tissue loss of AMPA receptors (AMPARs), and a specific mistrafficking of these AMPARs in PV+ interneurons in the stargazer somatosensory cortex. The current study was aimed at investigating if cellular changes in AMPAR expression were translated into deficits in receptors at specific synapses in the feedforward inhibitory microcircuit. Using western blot immunolabeling on biochemically isolated synaptic fractions, we demonstrate a loss of AMPAR GluA1–4 subunits in the somatosensory cortex of stargazers compared to non-epileptic control mice. Furthermore, using double post-embedding immunogold-cytochemistry, we show a loss of GluA1–4-AMPARs at excitatory synapses onto cortical PV+ interneurons. Altogether, these data indicate a loss of synaptic AMPAR-mediated excitation of cortical PV+ inhibitory neurons. As the cortex is considered the site of initiation of spike wave discharges (SWDs) within the corticothalamocortical circuitry, loss of AMPARs at cortical PV+ interneurons likely impairs feed-forward inhibitory output, and contributes to the generation of SWDs and absence seizures in stargazers.

show abstract

Synaptic changes in GABAA receptor expression in the thalamus of the stargazer mouse model of absence epilepsy

Cited by 23 publications

References 48 publications

NMDA Receptor Expression in the Thalamus of the Stargazer Model of Absence Epilepsy

NMDA Receptor Expression in the Thalamus of the Stargazer Model of Absence Epilepsy

Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse

Synaptic Changes in AMPA Receptor Subunit Expression in Cortical Parvalbumin Interneurons in the Stargazer Model of Absence Epilepsy

Contact Info

Product

Resources

About