Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice

Sabanov, Victor; Braat, Sien; D’Andrea, L.; Willemsen, Rob; Zeidler, Shimriet; Rooms, Liesbeth; Bagni, Claudia; Kooy, R. Frank; Balschun, Detlef

doi:10.1016/j.neuropharm.2016.12.010

Cited by 66 publications

(63 citation statements)

References 78 publications

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“…Thus, reduced tonic inhibitory control of dentate granule cells could negatively impact learning and memory as well as increase seizure susceptibility and levels of anxiety (Lee et al, 2016; Maguire et al, 2005; Whissell et al, 2013). A decrease in tonic inhibition has been found previously in other brain regions in mouse models of FXS, including the subiculum (Curia et al, 2009), basolateral nucleus of the amygdala (Martin et al, 2014; Olmos-Serrano et al, 2010), and the CA1 region of the hippocampus (Sabanov et al, 2016). The current findings support the suggestion that a decrease in tonic inhibition could be a common finding in FXS, occurring across multiple brain regions where the deficits could contribute to several behavioral features of FXS, including hyperexcitability, hypersensitivity, and increased seizure susceptibility (Martin et al, 2014; Paluszkiewicz et al, 2011; Whissell et al, 2015).…”

Section: Discussionsupporting

confidence: 54%

Decreased surface expression of the δ subunit of the GABA A receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome

Zhang

Peng

Tong

et al. 2017

Experimental Neurology

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While numerous changes in the GABA system have been identified in models of Fragile X Syndrome (FXS), alterations in subunits of the GABAA receptors (GABAARs) that mediate tonic inhibition are particularly intriguing. Considering the key role of tonic inhibition in controlling neuronal excitability, reduced tonic inhibition could contribute to FXS-associated disorders such as hyperactivity, hypersensitivity, and increased seizure susceptibility. The current study has focused on the expression and function of the δ subunit of the GABAAR, a major subunit involved in tonic inhibition, in granule cells of the dentate gyrus in the Fmr1 knockout (KO) mouse model of FXS. Electrophysiological studies of dentate granule cells revealed a marked, nearly four-fold, decrease in tonic inhibition in the Fmr1 KO mice, as well as reduced effects of two δ subunit-preferring pharmacological agents, THIP and DS2, supporting the suggestion that δ subunit-containing GABAARs are compromised in the Fmr1 KO mice. Immunohistochemistry demonstrated a small but statistically significant decrease in δ subunit labeling in the molecular layer of the dentate gyrus in Fmr1 KO mice compared to wildtype (WT) littermates. The discrepancy between the large deficits in GABA-mediated tonic inhibition in granule cells in the Fmr1 KO mice and only modest reductions in immunolabeling of the δ subunit led to studies of surface expression of the δ subunit. Cross-linking experiments followed by Western blot analysis demonstrated a small, non-significant decrease in total δ subunit protein in the hippocampus of Fmr1 KO mice, but a four-fold decrease in surface expression of the δ subunit in these mice. No significant changes were observed in total or surface expression of the α4 subunit protein, a major partner of the δ subunit in the forebrain. Postembedding immunogold labeling for the δ subunit demonstrated a large, three-fold, decrease in the number of symmetric synapses with immunolabeling at perisynaptic locations in Fmr1 KO mice. While α4 immunogold particles were also reduced at perisynaptic locations in the Fmr1 KO mice, the labeling was increased at synaptic sites. Together these findings suggest that, in the dentate gyrus, altered surface expression of the δ subunit, rather than a decrease in δ subunit expression alone, could be limiting δ subunit-mediated tonic inhibition in this model of FXS. Finding ways to increase surface expression of the δ subunit of the GABAAR could be a novel approach to treatment of hyperexcitability-related alterations in FXS.

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Section: Discussionsupporting

confidence: 54%

Decreased surface expression of the δ subunit of the GABA A receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome

Zhang

Peng

Tong

et al. 2017

Experimental Neurology

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“…Earlier work in both mouse and Drosophila FXS models showed impaired GABAergic circuit assembly and function. Recent mouse work shows FMRP binds multiple GABA A R mRNAs (although this is debated [73]), resulting in delay of the developmental GABA inhibitory switch in FMR1 knockouts [68]. In FXS mice, underdevelopment and reduction of many components of the GABAergic system occurs at an early age [73].…”

Section: Part Iv: New Progress In Excitatory/inhibitory (E/i) Balancementioning

confidence: 99%

“…Recent mouse work shows FMRP binds multiple GABA A R mRNAs (although this is debated [73]), resulting in delay of the developmental GABA inhibitory switch in FMR1 knockouts [68]. In FXS mice, underdevelopment and reduction of many components of the GABAergic system occurs at an early age [73]. For example, a GABA b R subunit (R1a) mediating presynaptic inhibition is reduced in FMR1 knockout mice [73].…”

Section: Part Iv: New Progress In Excitatory/inhibitory (E/i) Balancementioning

confidence: 99%

“…In FXS mice, underdevelopment and reduction of many components of the GABAergic system occurs at an early age [73]. For example, a GABA b R subunit (R1a) mediating presynaptic inhibition is reduced in FMR1 knockout mice [73]. Similarly, the Drosophila FXS model shows deficits in GABA b R suppression of presynaptic glutamate release [19].…”

Section: Part Iv: New Progress In Excitatory/inhibitory (E/i) Balancementioning

confidence: 99%

“…This early delay in GABA signaling is followed by later overelaboration of GABAergic neurons in a Drosophila brain learning/memory center [27]. In the mouse FXS model, recent work shows that both pre- and postsynaptic alterations cause abnormal GABA A R-mediated phasic inhibition [73], although GABAergic defects vary widely across brain regions [73]. In the Drosophila FXS model, GABAergic neuron structure and Ca 2+ signaling are both impaired, although correction of hypoinhibition is not sufficient to restore learning [27].…”

Section: Part Iv: New Progress In Excitatory/inhibitory (E/i) Balancementioning

confidence: 99%

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Multifarious Functions of the Fragile X Mental Retardation Protein

2017

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Fragile X syndrome (FXS), a heritable intellectual and autism spectrum disorder, results from loss of Fragile X Mental Retardation Protein (FMRP). This neurodevelopmental disease state exhibits neural circuit hyperconnectivity and hyperexcitability. Canonically, FMRP functions as an mRNA-binding translation suppressor, but recent findings have enormously expanded proposed roles. Although connections between burgeoning FMRP functions remain unknown, recent advances have extended understanding of involvement in RNA-, channel- and protein-binding that modulates calcium signaling, activity-dependent critical period development and excitation-inhibition neural circuitry balance. This article contextualizes three years of FXS model research. Future directions extrapolated from recent advances focus on discovering links between FMRP roles; to determine whether FMRP has a multitude of unrelated functions, or combinatorial mechanisms can explain its multifaceted existence.

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Developmental onset of enduring long‐term potentiation in mouse hippocampus

et al. 2020

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Analysis of long-term potentiation (LTP) provides a powerful window into cellular mechanisms of learning and memory. Prior work shows late LTP (L-LTP), lasting >3 hr, occurs abruptly at postnatal day 12 (P12) in the stratum radiatum of rat hippocampal area CA1. The goal here was to determine the developmental profile of synaptic plasticity leading to L-LTP in the mouse hippocampus. Two mouse strains and two mutations known to affect synaptic plasticity were chosen: C57BL/6J and Fmr1 −/y on the C57BL/6J background, and 129SVE and Hevin −/− (Sparcl1 −/−) on the 129SVE background. Like rats, hippocampal slices from all of the mice showed test pulse-induced depression early during development that was gradually resolved with maturation by 5 weeks. All the mouse strains showed a gradual progression between P10-P35 in the expression of short-term potentiation (STP), lasting ≤1 hr. In the 129SVE mice, L-LTP onset (>25% of slices) occurred by 3 weeks, reliable L-LTP

show abstract

Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice

Cited by 66 publications

References 78 publications

Decreased surface expression of the δ subunit of the GABA A receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome

Decreased surface expression of the δ subunit of the GABA A receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome

Multifarious Functions of the Fragile X Mental Retardation Protein

Developmental onset of enduring long‐term potentiation in mouse hippocampus

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