Impaired dendritic spine maturation in GABAA receptor α1 subunit knock out mice

Heinen, Klaartje; Baker, Robert E.; Spijker, Sabine; Rosahl, Thomas W.; Pelt, Jaap van; Brussaard, Arjen B.

doi:10.1016/s0306-4522(03)00477-9

Cited by 41 publications

(35 citation statements)

References 44 publications

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“…Recent studies suggest that GABAergic signaling is involved in spine plasticity. GABA-A␣1 KO mice showed impaired spine maturation in adulthood (Heinen et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex

2016

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Dendritic spine turnover becomes limited in the adult cerebral cortex. Identification of specific aspects of spine dynamics that can be unmasked in adulthood and its regulatory molecular mechanisms could provide novel therapeutic targets for inducing plasticity at both the functional and structural levels for robust recovery from brain disorders and injuries in adults. Lynx1, an endogenous inhibitor of nicotinic acetylcholine receptors, was previously shown to increase its expression in adulthood and thus to limit functional ocular dominance plasticity in adult primary visual cortex (V1). However, the role of this "brake" on spine dynamics is not known. We examined the contribution of Lynx1 on dendritic spine turnover before and after monocular deprivation (MD) in adult V1 with chronic in vivo imaging using two-photon microscopy and determined the spine turnover rate of apical dendrites of layer 5 (L5) and L2/3 pyramidal neurons in adult V1 of Lynx1 knock-out (KO) mice. We found that the deletion of Lynx1 doubled the baseline spine turnover rate, suggesting that the spine dynamics in the adult cortex is actively limited by the presence of Lynx1. After MD, adult Lynx1-KO mice selectively exhibit higher rate of spine loss with no difference in gain rate in L5 neurons compared with control wild-type counterparts, revealing a key signature of spine dynamics associated with robust functional plasticity in adult V1. Overall, Lynx1 could be a promising therapeutic target to induce not only functional, but also structural plasticity at the level of spine dynamics in the adult brain.

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“…Recent studies suggest that GABAergic signaling is involved in spine plasticity. GABA-A␣1 KO mice showed impaired spine maturation in adulthood (Heinen et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex

2016

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“…The a1 subunit confers fast inhibitory properties, and as such, reducing prefrontal cortical GABA A a1 function can dampen sensitivity to local GABA release and augment long-term potentiation (eg, Lu et al, 2010). 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)).…”

Section: Discussionmentioning

confidence: 99%

“…We selectively knocked down the a1 subunit of the GABA A receptor, the predominant inhibitory ligand-gated ion channel in the brain. The a1 subunit confers fast inhibitory properties, and chronic knockdown increases the expression of immature filopodiallike dendritic spine protrusions that are unlikely to contain synapses, and also decreases the density of mature, mushroom-shaped spines in the cerebral cortex (Heinen et al, 2003). Diminished GABA A a1 expression and function are implicated in depression and other chronic stressor-related psychopathologies, and in utero cocaine exposure also downregulates GABA A a1 in rodent prefrontal cortex (Lu et al, 2009;Skilbeck et al, 2010;Hines et al, 2012), suggesting that GABA A a1 expression is a factor in disease risk or etiology.…”

Section: Introductionmentioning

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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“…It must, however, be remembered that other regulatory mechanisms are activated after the disruption of the ␣1 gene . These mechanisms may extend beyond the GABAergic system and beyond neurotransmitter signaling systems (Heinen et al, 2003;Reynolds et al, 2003). Related to tonic current is a study showing a K ϩ conductance increase in CGCs of mice lacking the ␣6 subunit of the GABA A receptor (Brickley et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Deletion of the GABA_AReceptor α1 Subunit Increases Tonic GABA_AReceptor Current: A Role for GABA Uptake Transporters

Ortinski

Turner²,

Barberis³

et al. 2006

J. Neurosci.

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The loss of more than half the number of GABA A receptors yet lack of pronounced phenotype in mice lacking the gene for the GABA A ␣1 subunit is somewhat paradoxical. We explored the role of tonic GABA A receptor-mediated current as a target of compensatory regulation in the ␣1 knock-out (Ϫ/Ϫ) mice. A 62% increase of tonic current was observed in the cerebellar granule cells ( Ϫ/Ϫ CGCs as a novel compensatory mechanism. Our data establish a role for GABA transporters as regulators of neuronal excitability in this and relevant models and examine other tonic conductance-regulating mechanisms responsible for the adaptive response of the cerebellar network to a deletion of a major synaptic GABA A receptor subunit.

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Impaired dendritic spine maturation in GABAA receptor α1 subunit knock out mice

Cited by 41 publications

References 44 publications

Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex

Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex

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

Deletion of the GABA_AReceptor α1 Subunit Increases Tonic GABA_AReceptor Current: A Role for GABA Uptake Transporters

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Impaired dendritic spine maturation in GABAA receptor α1 subunit knock out mice

Cited by 41 publications

References 44 publications

Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex

Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex

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

Deletion of the GABAAReceptor α1 Subunit Increases Tonic GABAAReceptor Current: A Role for GABA Uptake Transporters

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Deletion of the GABA_AReceptor α1 Subunit Increases Tonic GABA_AReceptor Current: A Role for GABA Uptake Transporters