Altered Cortical GABAA Receptor Composition, Physiology, and Endocytosis in a Mouse Model of a Human Genetic Absence Epilepsy Syndrome

Zhou, Chengwen; Huang, Zhenguang; Ding, Li; Deel, M. Elizabeth; Arain, Fazal Manzoor; Murray, Clark R.; Patel, Ronak S.; Flanagan, Christopher D.; Gallagher, Martín J.

doi:10.1074/jbc.m112.444372

Cited by 56 publications

(80 citation statements)

References 74 publications

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“…Mutations in specific subunits of the pentameric GABA A receptor have been found in probands of human pedigrees with absence epilepsy, and mice haploinsufficient for GABRA1, the GABA A receptor a 1 subunit, successfully recapitulated the human absence phenotype (Arain et al, 2012). Further investigation of this model found that Layer 6 pyramidal neurons are disinhibited but partially compensate by remodeling the channel with kinetically slower subunits (Zhou et al, 2013;Fig. 1).…”

Section: Gaba a Receptor Mutations: Fast Synaptic Disinhibitionmentioning

confidence: 98%

Monogenic models of absence epilepsy

Maheshwari

Noebels

2014

Progress in Brain Research

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Section: Gaba a Receptor Mutations: Fast Synaptic Disinhibitionmentioning

confidence: 98%

Monogenic models of absence epilepsy

Maheshwari

Noebels

2014

Progress in Brain Research

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“…Prolonged GABA A a1 deficiency can cause the proliferation of immature filopodial-like dendritic spine protrusions, and a loss of mature dendritic spines, the primary sites of excitatory synapses in the brain (Heinen et al, 2003). Prior studies concerning the effects of cortical GABA A a1 deficiency have largely utilized mice with unconditional heterozygous deletion of Gabra1 or forebrain-selective knockdown with early-life onset (eg, Kralic et al, (2002);Sonner et al, (2005); Zhou et al, (2013)). Instead, we knocked down GABA A a1 selectively in the cortex of mature mice.…”

Section: Discussionmentioning

confidence: 99%

“…Synaptic marker expression was reduced as early as 2 weeks following viral vector delivery, and in the absence of compensatory upregulation of GABA A a2 or GABA A a3. By contrast, GABA A a3 is upregulated following heterozygous deletion (Zhou et al, 2013). Mice with oPFC-targeted GABA A a1 knockdown were unable to select actions based on their consequences, developing instead habit-like behavioral inflexibility, recapitulating the effects of early-life cocaine exposure (Hinton et al, 2014) and chronic stressor exposure (Dias-Ferreira et al, 2009), among other manipulations modeling chronic psychiatric illness in rodents (reviewed by Schwabe et al, (2011);Schwabe and Wolf, (2013)).…”

Section: Discussionmentioning

confidence: 99%

GABAAα1-Mediated Plasticity in the Orbitofrontal Cortex Regulates Context-Dependent Action Selection

Swanson

Allen

Shapiro³

et al. 2014

Neuropsychopharmacol

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An essential aspect of goal-directed action selection is differentiating between behaviors that are more, or less, likely to be reinforced. Habits, by contrast, are stimulus-elicited behaviors insensitive to action-outcome contingencies and are considered an etiological factor in several neuropsychiatric disorders. Thus, isolating the neuroanatomy and neurobiology of goal-directed action selection on the one hand, and habit formation on the other, is critical. Using in vivo viral-mediated gene silencing, we knocked down Gabra1 in the orbitofrontal prefrontal cortex (oPFC) in mice, decreasing oPFC GABA A a1 expression, as well as expression of the synaptic marker PSD-95. Mice expressing Green Fluorescent Protein or Gabra1 knockdown in the adjacent M2 motor cortex served as comparison groups. Using instrumental response training followed by action-outcome contingency degradation, we then found that oPFC GABA A a1 deficiency impaired animals' ability to differentiate between actions that were more or less likely to be reinforced, though sensitivity to outcome devaluation and extinction were intact. Meanwhile, M2 GABA A a1 deficiency enhanced sensitivity to action-outcome relationships. Behavioral abnormalities following oPFC GABA A a1 knockdown were rescued by testing mice in a distinct context relative to that in which they had been initially trained. Together, our findings corroborate evidence that chronic GABA A a1 deficiency remodels cortical synapses and suggest that neuroplasticity within the healthy oPFC gates the influence of reward-related contextual stimuli. These stimuli might otherwise promote maladaptive habit-based behavioral response strategies that contribute to-or exacerbateneuropsychiatric illness.

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“…Mutations of GABA A receptors are associated with generalized epilepsy [91]. The GABA A receptor antibodies disrupt the GABA A receptor anchoring protein and reduce GABA A receptor inhibition in lengthy seizures, which lead to status epilepticus [92].…”

Section: Anti-gaba Receptor Encephalitismentioning

confidence: 99%

Paraneoplastic epilepsy

Serafini

Lukas

VanHaerents

et al. 2016

Epilepsy & Behavior

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Epilepsy can be a manifestation of paraneoplastic syndromes which are the consequence of an immune reaction to neuronal elements driven by an underlying malignancy affecting other organs and tissues. The antibodies commonly found in paraneoplastic encephalitis can be divided into two main groups depending on the target antigen: 1) antibodies against neuronal cell surface antigens, such as against neurotransmitter (N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), gamma-aminobutyric acid (GABA)) receptors, ion channels (voltage-gated potassium channel (VGKC)), and channel-complex proteins (leucine rich, glioma inactivated-1 glycoprotein (LGI1) and contactin-associated protein-2 (CASPR2)) and 2) antibodies against intracellular neuronal antigens (Hu/antineuronal nuclear antibody-1 (ANNA-1), Ma2/Ta, glutamate decarboxylase 65 (GAD65), less frequently to CV2/collapsin response mediator protein 5 (CRMP5)). In this review, we provide a comprehensive survey of the current literature on paraneoplastic epilepsy indexed by the associated onconeuronal antibodies. While a range of seizure types can be seen with paraneoplastic syndromes, temporal lobe epilepsy is the most common because of the association with limbic encephalitis. Early treatment of the paraneoplastic syndrome with immune modulation/suppression may prevent the more serious potential consequences of paraneoplastic epilepsy.

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Altered Cortical GABAA Receptor Composition, Physiology, and Endocytosis in a Mouse Model of a Human Genetic Absence Epilepsy Syndrome

Cited by 56 publications

References 74 publications

Monogenic models of absence epilepsy

Monogenic models of absence epilepsy

GABAAα1-Mediated Plasticity in the Orbitofrontal Cortex Regulates Context-Dependent Action Selection

Paraneoplastic epilepsy

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