Early depolarizing GABA controls critical-period plasticity in the rat visual cortex

Deidda, Gabriele; Allegra, Manuela; Cerri, Chiara; Naskar, Shovan; Bony, Guillaume; Zunino, Giulia; Bozzi, Yuri; Caleo, Matteo; Cancedda, Laura

doi:10.1038/nn.3890

Cited by 108 publications

(106 citation statements)

References 57 publications

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“…Owing to a low blood-brain barrier permeability and potential peripheral effects of bumetanide (see above), it remains unclear whether the described effects are causally related to an attenuation of cortical GABAergic depolarization. The same reasoning applies to the observation that systemic bumetanide application (P3-7) led to a moderate prolongation of the critical period of ocular dominance plasticity in rats (Deidda et al, 2015). In contrast to previous data, this effect was accompanied by a selective delay in the maturation of GABAergic synaptic transmission whereas the development of glutamatergic contacts, dendritic morphology and visual capabilities remained unaffected.…”

Section: Scenario 3: the Low Capacity Of Chloride Extrusion Enables Dsupporting

confidence: 53%

Functions of GABAergic transmission in the immature brain

Kirmse¹,

Holthoff

2017

E-Neuroforum

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γ-aminobutyric acid (GABA) mediates synaptic inhibition in the adult brain, but acts as a predominantly depolarizing and partially excitatory neurotransmitter in immature neurons. Recent in vivo studies have confirmed important aspects of this concept and at the same time provided clear evidence for mainly inhibitory GABA actions already in the neonatal cortex. First experimental data suggest that depolarizing responses to GABA might contribute to the activity-dependent maturation of neuronal circuits in vivo. Currently, however, a coherent picture of the role of GABAergic synapses in the immature brain cannot be drawn. Elucidating potential developmental functions of GABAergic depolarization therefore remains an important objective for future research.

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Section: Scenario 3: the Low Capacity Of Chloride Extrusion Enables Dsupporting

confidence: 53%

Functions of GABAergic transmission in the immature brain

Kirmse¹,

Holthoff

2017

E-Neuroforum

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“…Alterations in the polarity of GABAergic inhibition during early postnatal development through the NKCC1 antagonist bumetanide have been shown to prolong the duration of critical period plasticity in rat V1 (26). This effect can be rescued by concurrently increasing BDNF signaling by pharmacological means.…”

Section: Discussionmentioning

confidence: 99%

“…Increased intracellular chloride concentration and a change in the postsynaptic impact of GABAergic synapses have been demonstrated during development in mouse models of ASD, including fragile-X syndrome (23,24). Indirect evidence also points to this mechanism affecting RTT: Lower levels of KCC2 relative to NKCC1 have been found by immunoblot analysis of cerebrospinal fluid samples in patients with RTT (25); depolarizing GABAergic synapses in development follow from down-regulation of brain-derived neurotrophic factor (BDNF) (26), which is also an early consequence of MeCP2 deletion in mouse models (27); and insulin-like growth factor-1 (IGF1) treatment, which partially rescues behavioral and synaptic deficits in mutant mouse models of RTT (28,29), also activates KCC2 expression and restores the inhibitory action of GABAergic synapses in the hippocampus (30). Thus, the diverse effects of MeCP2 loss may include reducing inhibition via changes in GABA-mediated hyperpolarization.…”

Section: Significancementioning

confidence: 99%

“…To reconcile these observations, we hypothesized that the effectiveness of GABA as an inhibitory transmitter may be altered in gKO mice compared with WT animals. The development of GABAergic inhibitory transmission is associated with expression of neuronal cation-chloride cotransporters and an excitatory-toinhibitory shift in GABA polarity, which indeed is compromised in several mouse models of autism (23); furthermore, early developmental alteration of GABA polarity exerts a long-lasting effect on critical period plasticity in visual cortex (26).…”

Section: Gabaergic Neurotransmission Is Altered In Mecp2 Gko Mice Andmentioning

confidence: 99%

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Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Banerjee

Rikhye

Breton-Provencher

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

159

202

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Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging. and increases KCC2 expression to normalize the KCC2/NKCC1 ratio. Thus, loss of MeCP2 in the brain alters both excitation and inhibition in brain circuits via multiple mechanisms. Loss of MeCP2 from a specific interneuron subtype contributes crucially to the cell-specific and circuit-wide deficits of RTT. The joint restoration of inhibition and excitation in cortical circuits is pivotal for functionally correcting the disorder.MeCP2 | E/I balance | parvalbumin neurons | IGF1 | chloride transporters S ynaptic excitation (E) and inhibition (I), along with the neuronal balance of excitation and inhibition (E/I), is key to the function of brain circuits, and is often disrupted in neurodevelopmental disorders, including autism spectrum disorders (ASDs) (1-3). Rett syndrome (RTT) is a severe neurodevelopmental and adult disorder that arises from sporadic loss-of-function mutations in the X-linked (Xq28) methyl-CpG binding protein 2 gene (Mecp2) encoding the protein MeCP2 (4-7). MeCP2 is a critical regulator of brain development and adult neural function (8), and arrested brain maturation due to synaptic dysfunction is one of the hallmarks of RTT (3). However, the effects of MeCP2 on excitatory and inhibitory synaptic mechanisms in vivo, and on neuronal and circuit function underlying RTT pathophysiology, are unknown.MeCP2 is ubiquitously expressed in multiple cell types and subregions of the brain (4, 6, 9), including inhibitory interneurons, and has cell-autonomous as well as non-cell-autonomous effects (10); thus, it has been particularly challenging to identify its role in cell-specific brain circuits. Anatomically diverse inhibitory interneuron subtypes with distinct physiological signatures influence different aspects of neocortical function and behavior (11,12). Soma-targeting parvalbumin-expressing (PV + ) and dendritetargeting somatostatin-expressing (SOM + ) interneurons are the two major nonoverlapping populations of interneurons in mice that target cortical pyramidal neurons (13). Inhibition by PV + and SOM + neurons powerfully influences neuronal responses and circuit computations in visual cortex (14-17). Deletion of MeCP2 from all forebrain GABAergic interneurons recapitulates key aspects of RTT (18), demonstrating that altered inhibitory function is an important facet of RTT pathophysiology. Indeed, a major phenotype of MeCP2 reduction in individuals with RTT and in mouse models is ...

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“…By modulating spike timing-dependent forms of synaptic plasticity, GABA-mediated depolarization might have developmental effects independent of a gross change in overall activity levels. Interestingly, a recent study proposed that depolarizing GABAergic transmission during early development controls critical-period plasticity in rat visual cortex 64 . Collectively, our data reveal that GABA A R activation triggers membrane depolarization in the majority of upper CP neurons at P3-4 in vivo.…”

Section: Discussionmentioning

confidence: 99%

GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo

et al. 2015

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A large body of evidence from in vitro studies suggests that GABA is depolarizing during early postnatal development. However, the mode of GABA action in the intact developing brain is unknown. Here we examine the in vivo effects of GABA in cells of the upper cortical plate using a combination of electrophysiological and Ca 2 þ -imaging techniques. We report that at postnatal days (P) 3-4, GABA depolarizes the majority of immature neurons in the occipital cortex of anaesthetized mice. At the same time, GABA does not efficiently activate voltage-gated Ca 2 þ channels and fails to induce action potential firing. Blocking GABA A receptors disinhibits spontaneous network activity, whereas allosteric activation of GABA A receptors has the opposite effect. In summary, our data provide evidence that in vivo GABA acts as a depolarizing neurotransmitter imposing an inhibitory control on network activity in the neonatal (P3-4) neocortex.

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Early depolarizing GABA controls critical-period plasticity in the rat visual cortex

Cited by 108 publications

References 57 publications

Functions of GABAergic transmission in the immature brain

Functions of GABAergic transmission in the immature brain

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo

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