FOXP1 negatively regulates intrinsic excitability in D2 striatal projection neurons by promoting inwardly rectifying and leak potassium currents

Khandelwal, Nitin; Cavalier, Sheridan; Rybalchenko, Volodymyr; Kulkarni, Ashwinikumar; Anderson, Ashley G.; Konopka, Genevieve; Gibson, Jay R.

doi:10.1038/s41380-020-00995-x

Cited by 17 publications

(73 citation statements)

References 54 publications

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“…To our knowledge, no report is available on the functional significance of overexpressed FOXP1 in the NAc. However, based on the current findings, we hypothesize that the overexpression of FOXP1 at WD10 might further affect the maturation of intrinsic excitability of MSNs [ 109 ], thus regulating cellular composition and neurochemical architecture of the striatal circuitry during alcohol withdrawal metaplasticity [ 110 ].…”

Section: Discussionmentioning

confidence: 99%

Binge-like Alcohol Exposure in Adolescence: Behavioural, Neuroendocrine and Molecular Evidence of Abnormal Neuroplasticity… and Return

et al. 2021

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Binge alcohol consumption among adolescents affects the developing neural networks underpinning reward and stress processing in the nucleus accumbens (NAc). This study explores in rats the long-lasting effects of early intermittent exposure to intoxicating alcohol levels at adolescence, on: (1) the response to natural positive stimuli and inescapable stress; (2) stress-axis functionality; and (3) dopaminergic and glutamatergic neuroadaptation in the NAc. We also assess the potential effects of the non-intoxicating phytocannabinoid cannabidiol, to counteract (or reverse) the development of detrimental consequences of binge-like alcohol exposuredimensions. Our results show that adolescent binge-like alcohol exposure alters the sensitivity to positive stimuli, exerts social and novelty-triggered anxiety-like behaviour, and passive stress-coping during early and prolonged withdrawal. In addition, serum corticosterone and hypothalamic and NAc corticotropin-releasing hormone levels progressively increase during withdrawal. Besides, NAc tyrosine hydroxylase levels increase at late withdrawal, while the expression of dopamine transporter, D1 and D2 receptors xpression is dynamically altered during binge and withdrawal. Furthermore, the expression of markers of excitatory postsynaptic signaling —PSD95; Homer-1 and -2 and the activity-regulated spine-morphing proteins Arc, LIM Kinase 1 and FOXP1—increase at late withdrawal. Notably, subchronic cannabidiol, during withdrawal, attenuates social- and novelty-induced aversion and passive stress-coping and rectifies the hyper-responsive stress axis and NAc dopamine and glutamate-related neuroplasticity. Overall, the exposure to binge-like alcohol levels in adolescent rats makes the NAc, during withdrawal, a locus minoris resistentiae as a result of perturbations in neuroplasticity and in stress-axis homeostasis. Cannabidiol holds a promising potential for increasing behavioural, neuroendocrine and molecular resilience against binge-like alcohol level’s harmful effects.

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Section: Discussionmentioning

confidence: 99%

Binge-like Alcohol Exposure in Adolescence: Behavioural, Neuroendocrine and Molecular Evidence of Abnormal Neuroplasticity… and Return

et al. 2021

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“…A similar mechanism has been demonstrated for another key determinant of corticogenesis, autism susceptibility candidate-2 ( AUTS2 ; Hori et al, 2014 ). These studies revealed impairments in bioelectric properties of cortical neuronal populations and/or network activity upon loss of transcriptional regulators, illustrating that genetic determinants implicated in NDDs often link neuronal specification to cellular excitability (Huang and Hsueh, 2015 ; Rodríguez-Tornos et al, 2016 ; Khandelwal et al, 2021 ; Runge et al, 2021 ). In summary, Nr2f1 might influence cell excitability, either via the regulation of ion channels, or via the control of cytoskeletal components shaping neuronal structural features.…”

Section: Nr2f1 Regulates Cell Intrinsic Electrophysiological Properties During Neocortical Maturationmentioning

confidence: 96%

Structural and Functional Aspects of the Neurodevelopmental Gene NR2F1: From Animal Models to Human Pathology

Tocco

Bertacchi

Studer

2021

Front. Mol. Neurosci.

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The assembly and maturation of the mammalian brain result from an intricate cascade of highly coordinated developmental events, such as cell proliferation, migration, and differentiation. Any impairment of this delicate multi-factorial process can lead to complex neurodevelopmental diseases, sharing common pathogenic mechanisms and molecular pathways resulting in multiple clinical signs. A recently described monogenic neurodevelopmental syndrome named Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is caused by NR2F1 haploinsufficiency. The NR2F1 gene, coding for a transcriptional regulator belonging to the steroid/thyroid hormone receptor superfamily, is known to play key roles in several brain developmental processes, from proliferation and differentiation of neural progenitors to migration and identity acquisition of neocortical neurons. In a clinical context, the disruption of these cellular processes could underlie the pathogenesis of several symptoms affecting BBSOAS patients, such as intellectual disability, visual impairment, epilepsy, and autistic traits. In this review, we will introduce NR2F1 protein structure, molecular functioning, and expression profile in the developing mouse brain. Then, we will focus on Nr2f1 several functions during cortical development, from neocortical area and cell-type specification to maturation of network activity, hippocampal development governing learning behaviors, assembly of the visual system, and finally establishment of cortico-spinal descending tracts regulating motor execution. Whenever possible, we will link experimental findings in animal or cellular models to corresponding features of the human pathology. Finally, we will highlight some of the unresolved questions on the diverse functions played by Nr2f1 during brain development, in order to propose future research directions. All in all, we believe that understanding BBSOAS mechanisms will contribute to further unveiling pathophysiological mechanisms shared by several neurodevelopmental disorders and eventually lead to effective treatments.

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“…In conclusion, the electrophysiological maturation of striatal neurons during the postnatal period is associated with changes in intrinsic excitability and excitatory and inhibitory synaptogenesis (Cazorla et al, 2012;Kozorovitskiy et al, 2012Kozorovitskiy et al, , 2015Lieberman et al, 2018;Kuo and Liu, 2019). Recent work aimed at defining the mechanisms that control striatal maturation have focused on the SPN and have highlighted a role for circuit mechanisms (Kozorovitskiy et al, 2012), neuromodulation (Kozorovitskiy et al, 2015;Lieberman et al, 2018), and cell-autonomous pathways that contribute to postnatal development of these cells (Oldenburg and Ding, 2011;Peixoto et al, 2016Peixoto et al, , 2019Guevara et al, 2020;Lieberman et al, 2020;Khandelwal et al, 2021). Here, we extend this analysis by focusing on striatal ChIs, neurons that are thought to play central roles in striatal action and sensorimotor learning.…”

Section: Maturation Of Da Release Properties Depends On Cholinergic Signalingmentioning

confidence: 99%

Coordinated Postnatal Maturation of Striatal Cholinergic Interneurons and Dopamine Release Dynamics in Mice

et al. 2021

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Dynamic changes in motor abilities and motivated behaviors occur during the juvenile and adolescent periods. The striatum is a subcortical nucleus critical to action selection, motor learning, and reward processing. Its tonically active cholinergic interneuron (ChI) is an integral regulator of the synaptic activity of other striatal neurons, as well as afferent axonal projections of midbrain dopamine (DA) neurons; however, little is known about its development. Here, we report that ChI spontaneous activity increases during postnatal development of male and female mice, concomitant with a decreased afterhyperpolarization (AHP). We characterized the postnatal development of four currents that contribute to the spontaneous firing rate of ChIs, including I SK , I A , I h , and I NaP . We demonstrated that the developmental increase in I NaP drives increased ChI firing rates during the postnatal period and can be reversed by the I NaP inhibitor, ranolazine. We next addressed whether immature cholinergic signaling may lead to functional differences in DA release during the juvenile period. In the adult striatum, nicotinic acetylcholine receptors (nAChRs) prevent linear summation of DA release in response to trains of high-frequency stimuli. We show that, in contrast, during the second postnatal week, DA release linearly sums with trains of high-frequency stimuli. Consistently, nAChR antagonists exert little effect on dopamine release at postnatal day (P)10, but enhance the summation of evoked DA release in mice older than postnatal day P28. Together, these results reveal that postnatal maturation of ChI activity is due primarily to enhanced I NaP and identify an interaction between developing cholinergic signaling and DA neurotransmission in the juvenile striatum.

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FOXP1 negatively regulates intrinsic excitability in D2 striatal projection neurons by promoting inwardly rectifying and leak potassium currents

Cited by 17 publications

References 54 publications

Binge-like Alcohol Exposure in Adolescence: Behavioural, Neuroendocrine and Molecular Evidence of Abnormal Neuroplasticity… and Return

Binge-like Alcohol Exposure in Adolescence: Behavioural, Neuroendocrine and Molecular Evidence of Abnormal Neuroplasticity… and Return

Structural and Functional Aspects of the Neurodevelopmental Gene NR2F1: From Animal Models to Human Pathology

Coordinated Postnatal Maturation of Striatal Cholinergic Interneurons and Dopamine Release Dynamics in Mice

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