Enhanced Infragranular and Supragranular Synaptic Input onto Layer 5 Pyramidal Neurons in a Rat Model of Cortical Dysplasia

Brill, Julia; Huguenard, John R.

doi:10.1093/cercor/bhq040

Cited by 34 publications

(27 citation statements)

References 69 publications

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“…Increased synaptically-evoked TC amplitude and unchanged uncaging-evoked TC amplitude together suggest that there are changes in endogenous glutamate release rather than astrocyte glutamate uptake. In line with this hypothesis, the threshold to evoke a synaptic TC was significantly lower in the FL cortex, indicating that neuronal glutamatergic inputs are increased in number or that ascending axons are more easily activated (Brill and Huguenard, 2010; Dulla et al, 2012; Jacobs et al, 1999c). The delayed onset of synaptically-evoked TCs in the microgyrus also supports a model of FL pathology which includes large-scale reorganization of afferent excitatory fibers (Jacobs et al, 1999b; Jacobs et al, 1999c).…”

Section: Discussionsupporting

confidence: 59%

Astrocyte membrane properties are altered in a rat model of developmental cortical malformation but single-cell astrocytic glutamate uptake is robust

Hanson

Danbolt

Dulla

2016

Neurobiology of Disease

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Developmental cortical malformations (DCMs) are linked with severe epilepsy and are caused by both genetic and environmental insults. DCMs include several neurological diseases, such as focal cortical dysplasia, polymicrogyria, schizencephaly, and others. Human studies have implicated astrocyte reactivity and dysfunction in the pathophysiology of DCMs, but their specific role is unknown. As astrocytes powerfully regulate glutamate neurotransmission, and glutamate levels are known to be increased in human epileptic foci, understanding the role of astrocytes in the pathological sequelae of DCMs is extremely important. Additionally, recent studies examining astrocyte glutamate uptake in DCMs have reported conflicting results, adding confusion to the field. In this study we utilized the freeze lesion (FL) model of DCM, which is known to induce reactive astrocytosis and cause significant changes in astrocyte morphology, proliferation, and distribution. Using whole-cell patch clamp recording from astrocytes, we recorded both UV-uncaging and synaptically evoked glutamate transporter currents (TCs), widely accepted assays of functional glutamate transport by astrocytes. With this approach, we set out to test the hypothesis that astrocyte membrane properties and glutamate transport were disrupted in this model of DCM. Though we found that the developmental maturation of astrocyte membrane resistance was disrupted by FL, glutamate uptake by individual astrocytes was robust throughout FL development. Interestingly, using an immunolabeling approach, we observed spatial and developmental differences in excitatory amino acid transporter (EAAT) expression in FL cortex. Spatially specific differences in EAAT2 (GLT-1) and EAAT1 (GLAST) expression suggest that the relative contribution of each EAAT to astrocytic glutamate uptake may be altered in FL cortex. Lastly, we carefully analyzed the amplitudes and onset times of both synaptically- and UV uncaging-evoked TCs. We found that in the FL cortex, synaptically-evoked, but not UV uncaging-evoked TCs, were larger in amplitude. Additionally, we found that the amount of electrical stimulation required to evoke a synaptic TC was significantly reduced in the FL cortex. Both of these finding are consistent with increased excitatory input to the FL cortex, but not with changes in how individual astrocytes remove glutamate. Taken together, our results demonstrate that the maturation of astrocyte membrane resistance, local distribution of glutamate transporters, and glutamatergic input to the cortex are altered in the FL model, but that single-cell astrocytic glutamate uptake is robust.

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Section: Discussionsupporting

confidence: 59%

Astrocyte membrane properties are altered in a rat model of developmental cortical malformation but single-cell astrocytic glutamate uptake is robust

Hanson

Danbolt

Dulla

2016

Neurobiology of Disease

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“…Surprisingly, the age of onset for increased susceptibility does not match the timing of one of the previously identified potential epileptogenic mechanisms, that of increased excitatory afferents to layer V pyramidal neurons (Zsombok and Jacobs, 2007). We have also suggested that alterations occur in specific interneuron subtypes (George and Jacobs, 2006; George and Jacobs, 2011), and some effects on interneurons suggest anti-epileptogenic effects (Brill and Huguenard, 2010; Jacobs and Prince, 2005). Yet to be determined is the onset timing for these pro and anti-epileptogenic interneuron effects.…”

Section: Discussionmentioning

confidence: 91%

Early susceptibility for epileptiform activity in malformed cortex

Bell

Jacobs

2014

Epilepsy Research

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Despite early disruption of developmental processes, hyperexcitability is often delayed after the induction of cortical malformations. In the freeze-lesion model of microgyria, interictal activity cannot be evoked in vitro until postnatal day (P)12, despite the increased excitatory afferent input to the epileptogenic region by P10. In order to determine the most critical time period for assessment of epileptogenic mechanisms, here we have used low-Mg2+ aCSF as a second hit after the neonatal freeze lesion to examine whether there is an increased susceptibility prior to the overt expression of epileptiform activity. This two-hit model produced increased interictal activity in freeze-lesioned relative to control cortex. We quantified this with measures of incidence by sweep, time to first epileptiform event, and magnitude of late activity. The increase was present even in the P7-9 survival group, befor increased excitatory afferents invade, as well as in the P10-11 and P12-15 groups. In our young adult group (P28-36), the amount of interictal activity did not differ, but only the lesioned cortices produced ictal activity. We conclude that epileptogenic processes begin early and continue beyond the expression of interictal activity, with different time courses for susceptibility for interictal and ictal activity.

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“…For example, in the isolated cortical slab, which produces epileptogenic insult (Fig. 5a), enhanced connectivity was restricted to infragranular layers, especially layer 5 93 ; however, in a model of focal cortical dysplasia, enhanced connectivity to layer 5 cells was seen from both infra and supra-granular regions 94 . These findings suggest that lesion-specific reorganization occurs in different injury models.…”

Section: Recurrent Excitationmentioning

confidence: 99%

Microcircuits and their interactions in epilepsy: is the focus out of focus?

2015

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Epileptic seizures represent dysfunctional neural networks dominated by excessive and/or hypersynchronous activity. Recent progress in the field has outlined two concepts regarding mechanisms of seizure generation or ictogenesis. First, all seizures, even those associated with what have historically been thought of as “primary generalized” epilepsies appear to originate within local microcircuits and then propagate from that initial ictogenic zone. Second, seizures propagate through cerebral networks and engage microcircuits in distal nodes—a process that can be weakened or even interrupted by suppressing activity in such nodes. Here, we describe various microcircuit motifs, with a special emphasis on one broadly implicated in several epilepsies - feed-forward inhibition. Further, we discuss how, in the dynamic network in which seizures propagate, focusing on circuit “choke points” remote from the initiation site might be as important as that of the initial dysfunction—the seizure “focus.”

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Enhanced Infragranular and Supragranular Synaptic Input onto Layer 5 Pyramidal Neurons in a Rat Model of Cortical Dysplasia

Cited by 34 publications

References 69 publications

Astrocyte membrane properties are altered in a rat model of developmental cortical malformation but single-cell astrocytic glutamate uptake is robust

Astrocyte membrane properties are altered in a rat model of developmental cortical malformation but single-cell astrocytic glutamate uptake is robust

Early susceptibility for epileptiform activity in malformed cortex

Microcircuits and their interactions in epilepsy: is the focus out of focus?

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