Elsevier

Experimental Neurology

Volume 306, August 2018, Pages 138-148
Experimental Neurology

Research Paper
Neurosteroid allopregnanolone reduces ipsilateral visual cortex potentiation following unilateral optic nerve injury

https://doi.org/10.1016/j.expneurol.2018.05.005Get rights and content

Highlights

  • Unilateral optic nerve crush induces ipsilateral potentiation of visual response.

  • Injury-induced potentiation exceeds stimulation-induced potentiation.

  • Unilateral optic nerve crush induces hyper-acuity in the intact eye.

  • Allopregnanolone abolishes injury-induced potentiation.

  • Injury-induced visual potentiation may result from cortical disinhibition.

Abstract

In adult mice with unilateral optic nerve crush injury (ONC), we studied visual response plasticity in the visual cortex following stimulation with sinusoidal grating. We examined visually evoked potentials (VEP) in the primary visual cortex ipsilateral and contralateral to the crushed nerve. We found that unilateral ONC induces enhancement of visual response on the side ipsilateral to the injury that is evoked by visual stimulation to the intact eye. This enhancement was associated with supranormal spatial frequency thresholds in the intact eye when tested using optomotor response. To probe whether injury-induced disinhibition caused the potentiation, we treated animals with the neurosteroid allopregnanolone, a potent agonist of the GABAA receptor, one hour after crush and on post-injury days 3, 8, 13, and 18.

Allopregnanolone diminished enhancement of the VEP and this effect was associated with the upregulated synthesis of the δ-subunit of the GABAA receptor. Our study shows a new aspect of experience-dependent plasticity following unilateral ONC. This hyper-activity in the ipsilateral visual cortex is prevented by upregulation of GABA inhibition with allopregnanolone. Our findings suggest the therapeutic potential of allopregnanolone for modulation of plasticity in certain eye and brain disorders and a possible role for disinhibition in ipsilateral hyper-activity following unilateral ONC.

Introduction

There is now good evidence that the adult visual cortex can undergo experience-dependent structural and functional modifications (Karmarkar and Dan, 2006; Gilbert and Li, 2012; Cooke and Bear, 2014; Kaneko and Stryker, 2017). One of the most extensively studied forms of experience-dependent changes is the effect of monocular visual deprivation (MD) on ocular dominance (OD) plasticity (Hofer et al., 2006; Gavornik and Bear, 2014). While normal mice show strong contralateral eye dominance, deprivation of visual input from the contralateral eye leads to weakening of the response from the deprived contralateral eye and strengthening of the response from the open ipsilateral eye (Frenkel and Bear, 2004; Smith and Bear, 2010).

Removal of visual input from an eye to the brain is induced not only by deprivation, but also by direct injury to the eye or optic nerve (Tagawa et al., 2005; Syken et al., 2006; Datwani et al., 2009; Nys et al., 2015a; Nys et al., 2015b). Most studies focus on changes in the visual cortex contralateral to the injured/enucleated/deprived eye, but it is important to note that a loss of visual input or damage to one hemisphere can also induce modifications of the other hemisphere through cortico-cortical (Van Brussel et al., 2011; Vasconcelos et al., 2011) and callosal connections (Restani et al., 2009; Laing et al., 2015).

A well-characterized animal model of optic nerve injury – optic nerve crush (ONC) – produces an acute insult that leads to retrograde degeneration of the vast majority of retinal ganglion cells and induces substantial functional reorganization in the brain (Sabel, 1999; Kreutz et al., 2004; Macharadze et al., 2012). The brain reorganization that accompanies optic nerve injury is more clinically relevant (optic neuropathies, glaucoma, optic nerve trauma) than monocular deprivation models, but it is understudied.

In this set of experiments we sought to determine how unilateral ONC injury affects both the contralateral and ipsilateral visual cortices of adult mice. We used a model of stimulus-selective response potentiation (SRP) to measure experience-dependent enhancement of cortical visually evoked potentials (VEP) on repeated presentation of a sinusoidal grating in a single orientation (Frenkel et al., 2006). We hypothesized that compared to MD, unilateral ONC will induce cortical enhancement of input from the intact eye, and consequently augmentation of cortical VEP ipsilateral to the intact eye (Sawtell et al., 2003; Frenkel et al., 2006). Since it was reported that OD plasticity is also associated with changes in visual behavior (Prusky et al., 2006; Iny et al., 2006), we measured the spatial frequency threshold following unilateral ONC with an optomotor test (Prusky et al., 2006; Tschetter et al., 2013).

Earlier studies on SRP and MD in adult rodents revealed that experience-dependent response enhancement in the visual cortex reflects strengthening of excitatory thalamo-cortical synaptic transmission in layer IV of the visual cortex (Frenkel et al., 2006; Coleman et al., 2010). To test whether post-ONC changes in VEP are also associated with increased excitatory transmission in thalamo-cortical synapses, we assessed expression of VGlut2, a vesicular glutamate transporter 2 specific to thalamo-cortical synapses (Nahmani and Erisir, 2005).

In contrast to the increased excitation observed after injury and in MD and SRP, cortical inhibition has been recently identified as a major determinant of normal sensory perception (Haider et al., 2013; Yazaki-Sugiyama et al., 2009; Smith and Bear, 2010; Chen et al., 2011; van Versendaal and Levelt, 2016). In this context, the role of GABA-active neurosteroids—positive modulators of GABAA receptors—in regulating inhibition has been established (Belelli and Lambert, 2005; Walker and Kullmann, 2012; Carver and Reddy, 2013). As an endogenous neurosteroid, allopregnanolone (ALLO) has been shown to increase inhibitory currents by activation of a wide range of GABAA receptors, particularly those containing the δ-subunit and considered responsible for tonic inhibition (Belelli and Lambert, 2005; Farrant and Nusser, 2005; Carver and Reddy, 2013; Reddy and Estes, 2016). ALLOhas also been shown to regulate expression and trafficking of the GABAA receptor subunits, leading to long-term inhibitory effects (Herd et al., 2007; Shen et al., 2005; Peng et al., 2009).

ALLO is one of the most potent positive modulators of cortical inhibition (Belelli and Lambert, 2005; Carver and Reddy, 2013; Crowley et al., 2016; Reddy and Estes, 2016) and has known neuroprotective properties (Djebaili et al., 2005; VanLandingham et al., 2006; Sayeed et al., 2009; Wang et al., 2010; Brinton, 2013; Irwin et al., 2014; Labombarda et al., 2013; Ishikawa et al., 2014; Guennoun et al., 2015). Given these properties, ALLO could be considered as a potential treatment for maladaptive cortical hyperexcitation. Pharmacological upregulation of GABAA-mediated inhibition by ALLO can also be used for mechanistic dissection of post-injury plasticity resulting from increased excitation and decreased inhibition. We further hypothesized that ONC-induced potentiation of cortical VEP can be altered by ALLO upregulation of GABAA-mediated inhibition. Reduction of potentiation by treatment with ALLO could suggest an involvement of GABAA-mediated disinhibition as one of the possible mechanisms of injury-induced potentiation in the visual cortex.

Section snippets

Animals

Young adult male C57BL/6 mice, 6 weeks of age, were obtained from the Jackson Laboratory (Bar Harbor, ME) and housed on a 12:12 h light:dark cycle with water and food access provided ad libitum. Procedures were approved by the Institutional Animal Care and Use Committee (Emory University protocol DAR-2003137-063018GN and Atlanta VA Medical Center protocol V008-13), and conformed to National Institutes of Health guidelines and the ARVO Statement for the Use of Animals in Ophthalmic and Vision

Experience-dependent enhancement of visual evoked response and enhancement of ipsilateral cortical function after unilateral ONC

Repetitive exposure to a stimulus with a single orientation induces potentiation of VEP amplitudes (known as the SRP) here operationally defined as a measure of experience-dependent plasticity in visual thalamo-cortical synapses (Frenkel et al., 2006).

Initially, because we were using chronically implanted skull screws instead of intracortical electrodes, we first validated our SRP model. We tested the VEPs recorded from skull screws over several recording days and clearly demonstrated the

Discussion

In this study we observed an enhanced response in the visual cortex ipsilateral to the ONC eye that was induced by input from the intact eye. The injury-induced enhancement in the intact pathway substantially exceeded the level of SRP in sham-operated animals and, in contrast to normal SRP, was independent of stimulus orientation: gratings of both familiar and novel orientation evoked high-amplitude VEP, while in sham animals, a novel stimulus presented on day 30 showed no augmentation from

Acknowledgments

The authors thank Leslie McCann for her invaluable editorial assistance in the preparation of the manuscript.

This work was funded by unrestricted gifts in support of research from The Marcus Foundation, and Allen and Company, and in part by the Emory University Eye Center Core Facilities and the Microscopy in Medicine Core (Emory School of Medicine, Division of Cardiology). National Institutes of Health (grant number P30 EY006360); the Department of Veterans Affairs Rehabilitation R&D Service

References (80)

  • M. Kaneko et al.

    Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex

    Neuron

    (2008)
  • U.R. Karmarkar et al.

    Experience-dependent plasticity in adult visual cortex

    Neuron

    (2006)
  • F. Labombarda et al.

    Neuroprotection by steroids after neurotrauma in organotypic spinal cord cultures: a key role for progesterone receptors and steroidal modulators of GABA(A) receptors

    Neuropharmacology

    (2013)
  • T.D. Mrsic-Flogel et al.

    Homeostatic regulation of eye-specific responses in visual cortex during ocular dominance plasticity

    Neuron

    (2007)
  • H.Y. Peng et al.

    Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABA(A) receptor subtypes

    Pain

    (2009)
  • D.S. Reddy et al.

    Clinical potential of neurosteroids for CNS disorders

    Trends Pharmacol. Sci.

    (2016)
  • L. Restani et al.

    Functional masking of deprived eye responses by callosal input during ocular dominance plasticity

    Neuron

    (2009)
  • J. Sautter et al.

    GM1 ganglioside treatment reduces visual deficits after graded crush of the rat optic nerve

    Brain Res.

    (1991)
  • N.B. Sawtell et al.

    NMDA receptor-dependent ocular dominance plasticity in adult visual cortex

    Neuron

    (2003)
  • I. Sayeed et al.

    Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism for better neuroprotective effects of allopregnanolone over progesterone

    Brain Res.

    (2009)
  • S. Schmidt et al.

    Age dependence of excitatory-inhibitory balance following stroke

    Neurobiol. Aging

    (2012)
  • H. Shen et al.

    Short-term steroid treatment increases delta GABAA receptor subunit expression in rat CA1 hippocampus: pharmacological and behavioral effects

    Neuropharmacology

    (2005)
  • G.B. Smith et al.

    Bidirectional ocular dominance plasticity of inhibitory networks: recent advances and unresolved questions

    Front. Cell. Neurosci.

    (2010)
  • L.O. Sun et al.

    Functional assembly of accessory optic system circuitry critical for compensatory eye movements

    Neuron

    (2015)
  • J.W. VanLandingham et al.

    The enantiomer of progesterone acts as a molecular neuroprotectant after traumatic brain injury

    Neuropharmacology

    (2006)
  • D. van Versendaal et al.

    Elimination of inhibitory synapses is a major component of adult ocular dominance plasticity

    Neuron

    (Apr 26 2012)
  • W.C. Abraham

    Metaplasticity: tuning synapses and networks for plasticity

    Nat. Rev. Neurosci.

    (2008)
  • R.S. Allen et al.

    Progesterone treatment in two rat models of ocular ischemia

    Invest. Ophthalmol. Vis. Sci.

    (2015)
  • R.S. Allen et al.

    Progesterone treatment shows greater protection in brain vs. retina in a rat model of middle cerebral artery occlusion: progesterone receptor levels may play an important role

    Restor. Neurol. Neurosci.

    (2016)
  • M.F. Bear

    Bidirectional synaptic plasticity: from theory to reality

    Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci.

    (2003)
  • D. Belelli et al.

    Neurosteroids: endogenous regulators of the GABA(a) receptor

    Nat. Rev. Neurosci.

    (2005)
  • B.R. Beston et al.

    Experience-dependent changes in excitatory and inhibitory receptor subunit expression in visual cortex

    Front. Synaptic Neurosci.

    (2010)
  • R.D. Brinton

    Neurosteroids as regenerative agents in the brain: therapeutic implications

    Nat. Rev. Endocrinol.

    (2013)
  • D. Cantu et al.

    Traumatic brain injury increases cortical glutamate network activity by compromising GABAergic control

    Cereb. Cortex

    (2015)
  • C.M. Carver et al.

    Neurosteroid interactions with synaptic and extrasynaptic GABA(A) receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

    Psychopharmacology

    (2013)
  • J.L. Chen et al.

    Structural basis for the role of inhibition in facilitating adult brain plasticity

    Nat. Neurosci.

    (2011)
  • K.K. Cho et al.

    The ratio of NR2A/B NMDA receptor subunits determines the qualities of ocular dominance plasticity in visual cortex

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

    (2009)
  • J.E. Coleman et al.

    Rapid structural remodeling of thalamocortical synapses parallels experience-dependent functional plasticity in mouse primary visual cortex

    J. Neurosci.

    (2010)
  • S.F. Cooke et al.

    Visual experience induces long-term potentiation in the primary visual cortex

    J. Neurosci.

    (2010)
  • S.F. Cooke et al.

    How the mechanisms of long-term synaptic potentiation and depression serve experience-dependent plasticity in primary visual cortex

    Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci.

    (2014)
  • Cited by (9)

    View all citing articles on Scopus
    View full text