Network burst activity in hippocampal neuronal cultures: the role of synaptic and intrinsic currents

Suresh, Jyothsna; Radojicic, Mihailo; Pesce, Lorenzo L.; Bhansali, Anita; Wang, Janice; Tryba, Andrew K.; Marks, Jeremy D.; Drongelen, Wim van

doi:10.1152/jn.00995.2015

Cited by 68 publications

(66 citation statements)

References 65 publications

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“…To test this, we pharmacologically blocked either AMPARs or NMDARs and compared the effect on control and KS neuronal network activity at DIV 28. In accordance with previous work 30,31 , we found in our control networks that acute treatment with an AMPAR antagonist (NBQX, 50 µM) abolished all network burst activity, whereas inhibiting NMDARs (D-AP5, 60 µM) only slightly decreased the network burst activity ( Fig. 4A, C).…”

Section: Increased Sensitivity To Nmda Receptor Antagonists In Ks Patsupporting

confidence: 93%

“…Previous studies on rodent-derived neuronal networks have shown that burst duration is directly influenced by AMPARs and NMDA receptors (NMDARs). Specifically, previous reports used receptor-type specific antagonists to show that AMPAR-driven bursts have short durations while NMDAR-driven bursts have comparatively longer durations 30 . We therefore hypothesized that increased NMDAR activity contributed to the lengthened bursts seen in KS networks.…”

Section: Increased Sensitivity To Nmda Receptor Antagonists In Ks Patmentioning

confidence: 99%

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Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling

Frega

Linda

Keller

et al. 2019

Preprint

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Epigenetic regulation of gene transcription plays a critical role in neural network development and in the etiology of Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). However, little is known about the mechanisms by which epigenetic dysregulation leads to neural network defects.Kleefstra syndrome (KS), caused by mutation in the histone methyltransferase EHMT1, is a neurodevelopmental disorder with the clinical features of both ID and ASD. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. In addition, we created an isogenic set by genetically editing healthy iPS cells. Characterization of the neurons at the single-cell and neuronal network level revealed consistent discriminative properties that distinguished EHMT1-mutant from wildtype neurons. Mutant neuronal networks exhibited network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes were mediated by the upregulation of the NMDA receptor (NMDAR) subunit 1 and correlate with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. Furthermore, we show that EHMT1 deficiency in mice leads to similar neuronal network impairments and increased NMDAR function. Finally, we could rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs.Together, our results demonstrate a direct link between EHMT1 deficiency in human neurons and NMDAR hyperfunction, providing the basis for a more targeted therapeutic approach to treating KS.Advances in human genetics over the past decade have resulted in the identification of hundreds of genes associated with intellectual disability (ID) and autism spectrum disorder (ASD) 1 . Within this group of newly identified genes the number of chromatin regulators is remarkably high 2-4 . These regulators are engaged in genome-wide covalent DNA modifications, post-translational modifications of histones, and control of genomic architecture and accessibility 5 . Several ASD/IDlinked chromatin regulators directly interact with one another to form larger complexes, regulating chromatin structure to control the expression of genes important for neurodevelopment and/or neuroplasticity 3 . Despite considerable progress in elucidating the genetic architecture of many neurodevelopmental disorders (NDDs), a large gap still exists between the genetic findings and deciphering the cellular or molecular pathobiology 6 . In particular, we require a better understanding of the relevance of genetic changes with respect to their downstream functional consequences and whether there is overlap between different patients within the clinical spectrum 6 .Kleefstra syndrome (KS) (OMIM#610253) is an example of a rare monogenic NDD with ID, ASD, hypotonia and dysmorphic features as hallmark phenotypes 7-9 . KS is caused by heterozygous de novo loss-of-functio...

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Section: Increased Sensitivity To Nmda Receptor Antagonists In Ks Patsupporting

confidence: 93%

Section: Increased Sensitivity To Nmda Receptor Antagonists In Ks Patmentioning

confidence: 99%

Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling

Frega

Linda

Keller

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…The blockade of GABA currents has previously been shown to not prevent the firing of NBs in cell culture networks [35,36,37]. Compared with the results in control conditions (i.e., unblocked GABA; “GABA-ON”), the blockade of inhibitory synapses in the model (GABA-OFF) caused an increase in the MFR, MBR, MFIB and a decrease in the MBD, both in our recordings and in simulations (Fig 3D; for further details see S5 Appendix).…”

Section: Resultsmentioning

confidence: 99%

Recurrently connected and localized neuronal communities initiate coordinated spontaneous activity in neuronal networks

et al. 2017

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Developing neuronal systems intrinsically generate coordinated spontaneous activity that propagates by involving a large number of synchronously firing neurons. In vivo, waves of spikes transiently characterize the activity of developing brain circuits and are fundamental for activity-dependent circuit formation. In vitro, coordinated spontaneous spiking activity, or network bursts (NBs), interleaved within periods of asynchronous spikes emerge during the development of 2D and 3D neuronal cultures. Several studies have investigated this type of activity and its dynamics, but how a neuronal system generates these coordinated events remains unclear. Here, we investigate at a cellular level the generation of network bursts in spontaneously active neuronal cultures by exploiting high-resolution multielectrode array recordings and computational network modelling. Our analysis reveals that NBs are generated in specialized regions of the network (functional neuronal communities) that feature neuronal links with high cross-correlation peak values, sub-millisecond lags and that share very similar structural connectivity motifs providing recurrent interactions. We show that the particular properties of these local structures enable locally amplifying spontaneous asynchronous spikes and that this mechanism can lead to the initiation of NBs. Through the analysis of simulated and experimental data, we also show that AMPA currents drive the coordinated activity, while NMDA and GABA currents are only involved in shaping the dynamics of NBs. Overall, our results suggest that the presence of functional neuronal communities with recurrent local connections allows a neuronal system to generate spontaneous coordinated spiking activity events. As suggested by the rules used for implementing our computational model, such functional communities might naturally emerge during network development by following simple constraints on distance-based connectivity.

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“…In general, hyperactivity in networks can be mediated by two major factors: a) changes in synaptic signaling between neurons resulting in altered E/I-balance; and b) changes in intrinsic electrophysiological properties of the neurons within the networks resulting e.g. in hyperexcitability (38). At the single cell level, we found in SMARCB1-, MLL3-and MBD5-deficient cultures a strong reduction in both excitatory and inhibitory synaptic inputs.…”

Section: Kss Gene-deficient Network Share a Common Mode Of Failurementioning

confidence: 73%

Distinct pathogenic genes causing intellectual disability and autism exhibit overlapping effects on neuronal network development

Frega¹,

Selten²,

Mossink³

et al. 2018

Preprint

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An intriguing question in medical biology is how mutations in functionally distinct genes can lead to similar clinical phenotypes. For example, patients with mutations in distinct epigenetic regulators EHMT1, MBD5, MLL3 or SMARCB1 share the core clinical features of intellectual disability (ID), autism spectrum disorder (ASD) and facial dysmorphisms. To elucidate how these phenotypic similarities are reflected by convergence at the molecular, cellular and neuronal network level, we directly compared the effects of their loss of function in neurons. Interestingly, knockdown of each gene resulted in hyperactive neuronal networks with altered patterns of synchronized activity. At the single-cell level, we found genotype-specific changes in intrinsic excitability and excitatory-inhibitory balance, but in all cases leading to increased excitability. Congruent with our physiological findings, we identified dysregulated genes that converge on biological and cellular pathways related to neuronal excitability and synaptic function, including genes previously implicated in ID/ASD. Yet, our data suggests that the common cellular phenotypes depend on the ensemble of dysregulated genes engaged in neuronal excitability rather than the direction of transcriptional changes of individual genes. The demonstration of increasing convergence from molecular pathways to neuronal networks may be a paradigm for other types of ID/ASD.

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Network burst activity in hippocampal neuronal cultures: the role of synaptic and intrinsic currents

Cited by 68 publications

References 65 publications

Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling

Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling

Recurrently connected and localized neuronal communities initiate coordinated spontaneous activity in neuronal networks

Distinct pathogenic genes causing intellectual disability and autism exhibit overlapping effects on neuronal network development

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