Partial ablation of frontal cortical subplate leads to developmental abnormalities in KCC2 in the prefrontal cortex

Lee, Kyla Gaeul; Rajakumar, Nagalingam

doi:10.1016/j.mcn.2022.103733

Cited by 2 publications

(2 citation statements)

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“…As neuronal maturation progresses, KCC2 expression increases, becoming the prominent Cl - extruder in mature neurons [ 13 – 15 ]. This shift in KCC2 and NKCC1 expression corresponds to a developmental transition from GABA-mediated depolarization to hyperpolarization [ 11 , 13 , 14 , 16 ]. Therefore, maintaining a balance between the activities of KCC2 and NKCC1 is crucial for GABAergic inhibition.…”

Section: Kcc2 and Chloride Homeostasismentioning

confidence: 99%

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment

McMoneagle,

Zhou,

Zhang

et al. 2023

Acta Pharmacol Sin

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Epilepsy is a prevalent neurological disorder characterized by unprovoked seizures. γ-Aminobutyric acid (GABA) serves as the primary fast inhibitory neurotransmitter in the brain, and GABA binding to the GABAA receptor (GABAAR) regulates Cl- and bicarbonate (HCO3-) influx or efflux through the channel pore, leading to GABAergic inhibition or excitation, respectively. The neuron-specific K+-Cl- cotransporter 2 (KCC2) is essential for maintaining a low intracellular Cl- concentration, ensuring GABAAR-mediated inhibition. Impaired KCC2 function results in GABAergic excitation associated with epileptic activity. Loss-of-function mutations and altered expression of KCC2 lead to elevated [Cl-]i and compromised synaptic inhibition, contributing to epilepsy pathogenesis in human patients. KCC2 antagonism studies demonstrate the necessity of limiting neuronal hyperexcitability within the brain, as reduced KCC2 functioning leads to seizure activity. Strategies focusing on direct (enhancing KCC2 activation) and indirect KCC2 modulation (altering KCC2 phosphorylation and transcription) have proven effective in attenuating seizure severity and exhibiting anti-convulsant properties. These findings highlight KCC2 as a promising therapeutic target for treating epilepsy. Recent advances in understanding KCC2 regulatory mechanisms, particularly via signaling pathways such as WNK, PKC, BDNF, and its receptor TrkB, have led to the discovery of novel small molecules that modulate KCC2. Inhibiting WNK kinase or utilizing newly discovered KCC2 agonists has demonstrated KCC2 activation and seizure attenuation in animal models. This review discusses the role of KCC2 in epilepsy and evaluates its potential as a drug target for epilepsy treatment by exploring various strategies to regulate KCC2 activity.

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Section: Kcc2 and Chloride Homeostasismentioning

confidence: 99%

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment

McMoneagle,

Zhou,

Zhang

et al. 2023

Acta Pharmacol Sin

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“…Mechanistically, delayed maturation of GABA function is implicated in certain abnormalities in the prefrontal cortex (PFC) and manifestations of schizophrenia (Schmidt and Mirnics, 2015 ; Luhmann et al, 2018 ). Recently, it was shown in neonatal rats that SPN ablation results in decreased immunoreactivity of potassium-chloride transporter proteins (KCC2)—responsible for the maturation of GABAergic synapses—in the PFC, suggesting a possible involvement of early SPN lesion in development of schizophrenia (Lee and Rajakumar, 2022 ).…”

Section: Early Environmental Insult and Pathophysiology Of The Subpla...mentioning

confidence: 99%

Changing subplate circuits: Early activity dependent circuit plasticity

Mukherjee

2023

Front. Cell. Neurosci.

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Early neural activity in the developing sensory system comprises spontaneous bursts of patterned activity, which is fundamental for sculpting and refinement of immature cortical connections. The crude early connections that are initially refined by spontaneous activity, are further elaborated by sensory-driven activity from the periphery such that orderly and mature connections are established for the proper functioning of the cortices. Subplate neurons (SPNs) are one of the first-born mature neurons that are transiently present during early development, the period of heightened activity-dependent plasticity. SPNs are well integrated within the developing sensory cortices. Their structural and functional properties such as relative mature intrinsic membrane properties, heightened connectivity via chemical and electrical synapses, robust activation by neuromodulatory inputs—place them in an ideal position to serve as crucial elements in monitoring and regulating spontaneous endogenous network activity. Moreover, SPNs are the earliest substrates to receive early sensory-driven activity from the periphery and are involved in its modulation, amplification, and transmission before the maturation of the direct adult-like thalamocortical connectivity. Consequently, SPNs are vulnerable to sensory manipulations in the periphery. A broad range of early sensory deprivations alters SPN circuit organization and functions that might be associated with long term neurodevelopmental and psychiatric disorders. Here we provide a comprehensive overview of SPN function in activity-dependent development during early life and integrate recent findings on the impact of early sensory deprivation on SPNs that could eventually lead to neurodevelopmental disorders.

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Partial ablation of frontal cortical subplate leads to developmental abnormalities in KCC2 in the prefrontal cortex

Cited by 2 publications

References 64 publications

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment

Changing subplate circuits: Early activity dependent circuit plasticity

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