Somatostatin Interneurons Promote Neuronal Synchrony in the Neonatal Hippocampus

Floßmann, Tom; Kaas, Thomas; Rahmati, Vahid; Kiebel, Stefan J.; Witte, Otto W.; Holthoff, Knut; Kirmse, Knut

doi:10.1016/j.celrep.2019.02.061

Cited by 46 publications

(60 citation statements)

References 47 publications

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“…One persistent hypothesis is that GABA, a largely inhibitory neurotransmitter in adults, depolarizes, and in some cases directly excites, young neurons as a result of their low expression of the neuronal K-Cl cotransporter KCC2 (6). According to this theory, early excitatory action of GABAergic neurons, primarily mediated by medial ganglion eminence-derived somatostatin-expressing neurons, drives synchronized activity in vitro (7,8) and supports glutamatergic and GABAergic synapse formation in cortical circuits (9,10). The switch of GABA's function from excitatory to inhibitory has further been hypothesized to drive the maturation of cortical activity patterns in vivo in human neonates and rodent neonates (2,11,12).…”

Section: Introductionmentioning

confidence: 99%

GABAergic interneurons excite neonatal hippocampus in vivo

Murata

2020

Sci. Adv.

106

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GABAergic interneurons are proposed to be critical for early activity and synapse formation by directly exciting, rather than inhibiting, neurons in developing hippocampus and neocortex. However, the role of GABAergic neurons in the generation of neonatal network activity has not been tested in vivo, and recent studies have challenged the excitatory nature of early GABA. By locally manipulating interneuron activity in unanesthetized neonatal mice, we show that GABAergic neurons are excitatory in CA1 hippocampus at postnatal day 3 (P3) and are responsible for most of the spontaneous firing of pyramidal cells at that age. Hippocampal interneurons become inhibitory by P7, whereas visual cortex interneurons are already inhibitory by P3 and remain so throughout development. These regional and age-specific differences are the result of a change in chloride reversal potential, because direct activation of light-gated anion channels in glutamatergic neurons drives CA1 firing at P3, but silences it at P7 in CA1, and at all ages in visual cortex. This study in the intact brain reveals that GABAergic interneuron excitation is essential for network activity in neonatal hippocampus and confirms that visual cortical interneurons are inhibitory throughout early postnatal development.

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Section: Introductionmentioning

confidence: 99%

GABAergic interneurons excite neonatal hippocampus in vivo

Murata

2020

Sci. Adv.

106

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“…As mentioned before, the high [Cl -]i in immature neurons and the resulting GABAergic [53,54] as well as excitatory actions [55][56][57]. However, it can be estimated that an attenuation of the GABAergic [Cl -]i depletion will prevent/ameliorate a loss of GABAergic excitation and will prevent/ameliorate an increase in the inhibitory effect of depolarizing GABAergic responses.…”

Section: Discussionmentioning

confidence: 99%

Coincident glutamatergic depolarizations enhance GABA_Areceptor-dependent Cl^-influx in mature and suppress Cl^-efflux in immature neurons

Lombardi

Jedlicka

Luhmann

et al. 2020

Preprint

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The impact of GABAergic transmission on neuronal excitability depends on the Cl--gradient across membranes. However, the Cl--fluxes through GABAA receptors alter the intracellular Cl- concentration ([Cl-]i) and in turn attenuate GABAergic responses, a process termed ionic plasticity. Recently it has been shown that coincident glutamatergic inputs significantly affect ionic plasticity. Yet how the [Cl-]i changes depend on the properties of glutamatergic inputs and their spatiotemporal relation to GABAergic stimuli is unknown. To investigate this issue, we used compartmental biophysical models of Cl- dynamics simulating either a simple ball-and-stick topology or a reconstructed immature CA3 neuron. These computational experiments demonstrated that glutamatergic co-stimulation enhances GABA receptor-mediated Cl- influx at low and attenuates or reverses the Cl- efflux at high initial [Cl-]i. The size of glutamatergic influence on GABAergic Cl--fluxes depends on the conductance, decay kinetics, and localization of glutamatergic inputs. Surprisingly, the glutamatergic shift in GABAergic Cl--fluxes is invariant to latencies between GABAergic and glutamatergic inputs over a substantial interval. In agreement with experimental data, simulations in a reconstructed CA3 pyramidal neuron with physiological patterns of correlated activity revealed that coincident glutamatergic synaptic inputs contribute significantly to the activity-dependent [Cl-]i changes. Whereas the influence of spatial correlation between distributed glutamatergic and GABAergic inputs was negligible, their temporal correlation played a significant role. In summary, our results demonstrate that glutamatergic co-stimulation had a substantial impact on ionic plasticity of GABAergic responses, enhancing the destabilization of GABAergic inhibition in the mature nervous systems, but suppressing GABAergic [Cl-]i changes in the immature brain. Therefore, glutamatergic shift in GABAergic Cl--fluxes should be considered as a relevant factor of short term plasticity.

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“…With paediatric patients it should be borne in mind that GABA may become a depolarizing neurotransmitter in the brain, and GABAergic inhibition can be a result of both membrane hyperpolarization and a stimulus. In such a case GABA can act as both a stimulatory and an inhibitory neurotransmitter in an immature brain (91,92).…”

Section: Neurosteroids and Seizure Activity In The Pediatric Populatimentioning

confidence: 99%

Neurosteroids and Seizure Activity

2020

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Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been continuously searched for. In this context, a group of endogenous or exogenous neurosteroids allosterically positively modulating GABA-A receptors may offer a promising approach. Among endogenous neurosteroids synthesized in the brain, allopregnanolone or allotetrahydrodeoxycorticosterone have been documented to exert anticonvulsant activity in a number of experimental models of seizures-pentylenetetrazol-, bicuculline-pilocarpine-, or 6 Hz-induced convulsions in rodents. Neurosteroids can also inhibit fully kindled seizures and some of them have been reported to counteract maximal electroshock-induced convulsions. An exogenous neurosteroid, alphaxalone, significantly elevated the threshold for maximal electroconvulsions in mice but it did not potentiate the anticonvulsive action of a number of conventional antiepileptic drugs against maximal electroshock-induced seizures. Androsterone not only elevated the threshold but significantly enhanced the protective action of carbamazepine, gabapentin and phenobarbital against maximal electroshock in mice, as well. Ganaxolone (a 3betamethylated analog of allopregnanolone) needs special consideration for two reasons. First, it performed better than conventional antiepileptic drugs, diazepam or valproate, in suppressing convulsive and lethal effects of pentylenetetrazol in pentylenetetrazol-kindled mice. Second, ganaxolone has been evaluated in the randomized, double-blind, placebocontrolled phase 2 trial in patients with intractable partial seizures, taking maximally 3 antiepileptic drugs. The initial results indicate that add-on therapy with ganaxolone resulted in reduced seizure frequency with adverse effect being mainly mild to moderate. Possibly, ganaxolone may be also considered against catamenial seizures. Some positive effects of ganaxolone as an adjuvant were also observed in children with refractory seizures and its use may also prove efficient for the management of neonatal seizures associated with hypoxic injury. Neurosteroids positively modulating GABA-A receptor complex exert anticonvulsive activity in many experimental models of seizures. Their interactions with antiepileptic drugs seem ambiguous in mice. Initial clinical data indicate that ganaxolone may provide a better seizure control in patients with drug-resistant epilepsy.

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Somatostatin Interneurons Promote Neuronal Synchrony in the Neonatal Hippocampus

Cited by 46 publications

References 47 publications

GABAergic interneurons excite neonatal hippocampus in vivo

GABAergic interneurons excite neonatal hippocampus in vivo

Coincident glutamatergic depolarizations enhance GABA_Areceptor-dependent Cl^-influx in mature and suppress Cl^-efflux in immature neurons

Neurosteroids and Seizure Activity

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Somatostatin Interneurons Promote Neuronal Synchrony in the Neonatal Hippocampus

Cited by 46 publications

References 47 publications

GABAergic interneurons excite neonatal hippocampus in vivo

GABAergic interneurons excite neonatal hippocampus in vivo

Coincident glutamatergic depolarizations enhance GABAAreceptor-dependent Cl-influx in mature and suppress Cl-efflux in immature neurons

Neurosteroids and Seizure Activity

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Coincident glutamatergic depolarizations enhance GABA_Areceptor-dependent Cl^-influx in mature and suppress Cl^-efflux in immature neurons