Developmental Changes of GABA Synaptic Transient in Cerebellar Granule Cells

Barberis, Andrea; Lu, Congyi; Vicini, Stefano; Mozrzymas, Jerzy W.

doi:10.1124/mol.104.006437

Cited by 25 publications

(14 citation statements)

References 36 publications

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“…We found that TPMPA similarly inhibited mIPSCs in control GFP and NLG-2 over-expressing CGCs both at DIV7-8 and DIV12-14 cultures (Fig 5). However, consistent with previous work (47), we did observe the differential inhibition of mIPSCs between young (DIV7-8) and old (DIV12-14) cultures (Fig 5A, B), suggesting a stronger presynaptic GABA release in young neurons. Together, these results may suggest that NLG-2 does not alter uniquantal GABA release, and the fast decay of mIPSC induced by NLG-2 was due to the differential expression of postsynaptic GABA A receptor subtypes.…”

Section: Resultssupporting

confidence: 93%

“…Of note, a prerequisite for an efficient displacement of competitive antagonist by synaptic agonist is that the dissociation time constant of the antagonist is comparable with the duration time of the GABA transient in synaptic cleft. TPMPA was found to be a suitable tool to reveal differences in the GABA transient in synaptic cleft due to its fast dissociation time constant of ~0.46ms (45-47). In this set of studies, GABAergic mIPSCs were recorded in absence and presence of TPMPA at two different culture ages, i.e.…”

Section: Resultsmentioning

confidence: 99%

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Neuroligin-2 accelerates GABAergic synapse maturation in cerebellar granule cells

Vicini

2009

Molecular and Cellular Neuroscience

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Neuroligins (NLGs) are postsynaptic cell adhesion molecules that are thought to function in synaptogenesis. To investigate the role of NLGs on synaptic transmission once the synapse is formed, we transfected neuroligin-2(NLG2) in cultured mouse cerebellar granule cells (CGCs), and recorded GABA A (γ-aminobutyric acid) receptor mediated miniature postsynaptic currents (mISPCs). NLG2 transfected cells had mIPSCs with faster decay than matching GFP expressing controls at young culture ages (days in vitro, DIV 7-8). Down-regulation of NLG2 by the isoform specific shRNA-NLG2 resulted in an opposite effect. We and others have shown that the switch of α subunits of GABA A Rs from α2/3 to α1 underlies developmental speeding of the IPSC decay in various CNS regions, including the cerebellum. To assess whether the reduced decay time of mIPSCs by NLG2 is due to the recruitment of more α1 containing GABA A Rs at the synapses, we examined the prolongation of current decay by the zolpidem, which has been shown to preferentially enhance the activity of α1 subunit containing GABA channel. The application of zolpidem resulted in a significantly greater prolongation kinetics of synaptic currents in NLG2 over-expressing cells than control cells, suggesting that NLG2 over-expression accelerates synapse maturation by promoting incorporation of the α1 subunit-containing GABA A Rs at postsynaptic sites in immature cells. In addition, the effect of NLG2 on the speeding of decay time course of synaptic currents was abolished when we used CGC cultures from α1-/-mice. Lastly, to exclude the possibility that the fast decay of mIPSCs induced by NLG2 could be also due to the impacts of NLG2 on the GABA transient in synaptic cleft, we measured the sensitivity of mIPSCs to the fast-off competitive antagonists TPMPA. We found that TPMPA similarly inhibits mIPSCs in control and NLG2 over-expressing CGCs both at young age (DIV8) and old age (DIV14) of cultures. However, we confirm our previous finding of a greater inhibition of mIPSCs in young (DIV8) than more mature (DIV14) cultures. Together, our results suggest that NLG2 does not alter uniquantal GABA release, and the fast decay of mIPSC induced by NLG2 is due to the differential expression of postsynaptic GABA A receptor subtypes. Taken all together, we propose that NLG-2 plays important functional role in inhibitory synapse development and maturation.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Neuroligin-2 accelerates GABAergic synapse maturation in cerebellar granule cells

Vicini

2009

Molecular and Cellular Neuroscience

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“…For these experiments we examined the effect of TPMPA, a low-affinity competitive GABA A receptor antagonist. The block of postsynaptic GABA A receptor-mediated responses is dependent upon GABA concentration at the synapse (Barberis et al, 2005; Szabadics et al, 2007). When synaptic GABA levels are low, TPMPA is displaced from postsynaptic receptors to a lesser extent, and thus IPSCs are more effectively blocked.…”

Section: Resultsmentioning

confidence: 99%

Defective GABAergic Neurotransmission and Pharmacological Rescue of Neuronal Hyperexcitability in the Amygdala in a Mouse Model of Fragile X Syndrome

Olmos-Serrano¹,

Paluszkiewicz²,

Martin³

et al. 2010

Journal of Neuroscience

283

310

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Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by variable cognitive impairment and behavioral disturbances such as exaggerated fear, anxiety and gaze avoidance. Consistent with this, findings from human brain imaging studies suggest dysfunction of the amygdala. Underlying alterations in amygdala synaptic function in the Fmr1 knock-out (KO) mouse model of FXS, however, remain largely unexplored. Utilizing a combination of approaches, we uncover profound alterations in inhibitory neurotransmission in the amygdala of Fmr1 KO mice. We demonstrate a dramatic reduction in the frequency and amplitude of phasic IPSCs, tonic inhibitory currents, as well as in the number of inhibitory synapses in Fmr1 KO mice. Furthermore, we observe significant alterations in GABA availability, both intracellularly and at the synaptic cleft. Together, these findings identify abnormalities in basal and action potentialdependent inhibitory neurotransmission. Additionally, we reveal a significant neuronal hyperexcitability in principal neurons of the amygdala in Fmr1 KO mice, which is strikingly rescued by pharmacological augmentation of tonic inhibitory tone using the GABA agonist gaboxadol (THIP). Thus, our study reveals relevant inhibitory synaptic abnormalities in the amygdala in the Fmr1 KO brain and supports the notion that pharmacological approaches targeting the GABAergic system may be a viable therapeutic approach toward correcting amygdala-based symptoms in FXS.

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“…In particular, the decay time constants of remaining receptors are prolonged, reflecting the substitution of a1-GABA A receptors by another subtype. Since a1-GABA A receptors have faster kinetics than those containing the a2 or a3 subunits (88,89), this factor was taken as an index for the sustained presence of these subunits in mature granule cells of mutant mice (87,90).…”

Section: Effects Of Targeted Subunit Gene Deletion On Cerebellar Gabamentioning

confidence: 99%

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

Fritschy

Panzanelli

2006

Cerebellum

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GABA A receptors form heteromeric GABA-gated chloride channels assembled from a large family of subunit genes. In cerebellum, distinct GABA A receptor subtypes, differing in subunit composition, are segregated between cell types and synaptic circuits. The cerebellum therefore represents a useful system to investigate the significance of GABA A receptor heterogeneity. For instance, studies of mice carrying targeted deletion of major GABA A receptor subunit genes revealed the role of a subunit variants for receptor assembly, synaptic targeting, and functional properties. In addition, these studies unraveled mandatory association between certain subunits and demonstrated distinct pharmacology of receptors mediating phasic and tonic inhibition. Although some of these mutants have a profound loss of GABA A receptors, they exhibit only minor impairment of motor function, suggesting activation of compensatory mechanisms to preserve inhibitory networks in the cerebellum. These adaptations include an altered balance between phasic and tonic inhibition, activation of voltageindependent K + conductances, and upregulation of GABA A receptors in interneurons that are not affected directly by the mutation. Deletion of the a1 subunit gene leads to complete loss of GABA A receptors in Purkinje cells. A striking alteration occurs in these mice, whereby presynaptic GABAergic terminals are preserved in the molecular layer but make heterologous synapses with spines, characterized by a glutamatergic-like postsynaptic density. During development of a1 0/0 mice, GABAergic synapses are initially formed but are replaced upon spine maturation. These findings suggest that functional GABA A receptors are required for long-term maintenance of GABAergic synapses in Purkinje cells.

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Developmental Changes of GABA Synaptic Transient in Cerebellar Granule Cells

Cited by 25 publications

References 36 publications

Neuroligin-2 accelerates GABAergic synapse maturation in cerebellar granule cells

Neuroligin-2 accelerates GABAergic synapse maturation in cerebellar granule cells

Defective GABAergic Neurotransmission and Pharmacological Rescue of Neuronal Hyperexcitability in the Amygdala in a Mouse Model of Fragile X Syndrome

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

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