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date: 18 March 2019

Pharmacological Manipulation of Critical Period Plasticity

Abstract and Keywords

Neuronal networks are refined through an activity-dependent competition during critical periods of early postnatal development. Recent studies have shown that critical period plasticity is influenced by a number of environmental factors, including drugs that are widely used for the treatment of brain disorders. These findings suggest a new paradigm, where pharmacological treatments can be used to open critical period–like plasticity in the adult brain. The plastic networks can then be modified through rehabilitation or psychotherapy to rewire those abnormally wired during development. This kind of combination of pharmacotherapy with physical or psychological rehabilitation may open a new opportunity for a more efficient recovery of a number of neurological and neuropsychiatric disorders.

Keywords: Critical periods, visual cortex, BDNF, extracellular matrix, antidepressants, HDAC inhibitors, GABA, catecholamines

Critical periods are defined as time windows during late stages of development when the brain is especially sensitive to adapt to certain information from the environment. From a functional point of view, two factors are especially important for critical period plasticity: first, the state of plasticity of the brain or a particular network, and second, the external or internal context that drives input activity for the network. The existence of both of these at the same time leads to effective changes in the neural network. An example to illustrate this principle is that the absence of the specific stimuli as language exposure during the critical period for language acquisition leads to deficits in adulthood (as in the case of feral children). Once that time window of plasticity is closed, the exposure to language does not result in normal language acquisition (Newport, 1990).

The most widely studied experimental model of critical period plasticity is the mammalian visual system. The groundbreaking work of Hubel and Wiesel showed how information arriving from different eyes competes for target innervation in the visual cortex. During early developmental stages, inputs from each eye are kept separated in the lateral geniculate nucleus of thalamus. Thalamic inputs representing each eye initially overlap extensively when they innervate the visual cortex. During the postnatal critical period, inputs from each eye segregate from each other to form ocular dominance columns where inputs from one eye predominate and proliferate, whereas the inputs from the other eye are withdrawn. Hubel and Wiesel demonstrated that proper segregation requires balanced use of both eyes: while in normal animals and humans, columns of ocular dominance representing each eye are evenly distributed, inactivity of inputs from one eye (due to cataract, refraction defect, or strabismus) leads to the shrinkage of columns innervated by that eye of the visual cortex, rendering that eye amblyopic. The time window during which this segregation effectively takes place is known as the critical or sensitive period, which in the visual cortex ends at about 35 days of age in mice, 12 weeks in kittens, and five years in humans (Gordon & Stryker, 1996).

Although the biology related to critical periods is typically investigated in primary sensory cortices, it has become obvious that critical periods exist not only in sensory domains, but also in networks related to “higher” brain functions such as language and social learning (Newport, 1990), and they are considered a universal property of developing neural networks. It is widely assumed that an activity-dependent refinement of initially coarse innervation into organized representations takes place in all neuronal networks (Bardin, 2012); however, direct evidence for such organization is difficult to attain outside the primary sensory areas. In this chapter, we will first discus the information related to manipulations of the sensory systems and then proceed to data regarding other networks, such as the fear system.

Critical periods have become an expanding area of research during the last decade (Box 1). Although the existence of critical periods has been known since the times of Mountcastle and Hubel and Wiesel, more than 60 years ago, it has only recently become apparent that critical period–like plasticity can be manipulated pharmacologically, to either anticipate or delay its natural timing, or more interestingly, to reopen it during adulthood. Studies in experimental animals have provided evidence that pharmacological manipulation can lengthen or suppress the naturally occurring critical periods, and that critical period–like plasticity can be pharmacologically activated in adulthood. There is indirect evidence that pharmacological agents may also regulate critical period plasticity in the human brain; however, attempts to test this hypothesis directly have produced controversial results.

Manipulations During the Developmental Critical Period

In attempts to investigate the mechanisms undelying critical period plasticity, the effects of several drug classes as well as other manipulations have been tested on their effects on plasticity during the critical periods.

GABA

Intracortical inhibition matures rapidly during the first weeks of life, achieving the peak of inhibitory synapses at day 20 in the visual cortex of mice (Blue & Parnavelas, 1983), around the same time that the classically defined visual critical period opens (Gordon & Stryker, 1996). Moreover, further maturation of cortical inhibition coincides with the closure of critical periods.

Indeed, one of the most widely studied factors in regard to critical period plasticity has been the neurotransmitter gamma aminobutyric acid (GABA), which is the main mediator of inhibitory neurotransmission in the brain. Early studies on the role of GABAergic innervation showed that the infusion of the GABAA receptor agonist muscimol into the visual cortex during the critical period while one of the eyes was patched (monocular deprivation; MD) blocked the shift of ocular dominance towards the open eye afterwards (Reiter & Stryker, 1988) (Table 1). Under those same experimental conditions, it was shown that the thalamic axons representing the input of the open eye were shrunk (Hata, Tsumoto, & Stryker, 1999).

In this same line, Fagiolini and Hensch (2000) hypothesized that inhibitory connectivity might trigger the opening of critical period plasticity. They engineered mice lacking one of the isoforms of the enzyme responsible for the synthesis of GABA (GAD65) and showed that reduced inhibition prevents the opening of a critical period plasticity window (Fagiolini & Hensch, 2000). Diazepam, an enhancer of GABA receptor function, can trigger the opening of critical period plasticity in these knockout (KO) mice at any time, and accelerate the start and closure of the critical period in normal mice if infused before the start of the critical period (Table 1).

These observations have led to the idea that there is a range of inhibition that allows critical period plasticity, higher than the pre-critical period levels but lower than those present in the adult brain (Sale, Berardi, Spolidoro, Baroncelli, & Maffei, 2010). In line with this, drugs that decrease GABA levels, such as the antagonist of GABAA receptor bicuculline, have been shown to impair ocular dominance plasticity during the naturally occurring critical period (Ramoa, Paradiso, & Freeman, 1988), delaying the start of the critical period.

GABA has also been shown to influence the properties of the critical period in the fear system. During its critical period, before weaning (around P23), memories extinguish easily in what is known as infantile amnesia (Campbell & Campbell, 1962), a period hypothesized to allow the development of attachment to the mother regardless of fear-related memories (Landers & Sullivan, 2012). Renewal of extinguished memories fails at P16, and only from P23 onwards can it successfully trigger fear memories. This process can be reverted by using a GABA inverse agonist, FG7142, allowing younger animals to renew extinguished fear memories (Kim & Richardson, 2007), which fits with the model suggested by Fagiolini and Hensch for the visual cortex, in which increased GABA accelerates the start and closure of the critical period.

Several factors have been suggested when considering the mechanisms through which GABA modulates the timing of the critical period. Special focus has been given to different extracellular matrix components that modulate the activity of different interneuronal subpopulations.

Extracellular Matrix Components

PSA-NCAM

The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is a post-translational modification expressed throughout the brain during development (Oltmann-Norden et al., 2008). Its canonical function is hypothesized to create a de-adhesive environment surrounding neurons expressing the molecule, helping growth of projecting axons or cell migration (Rutishauser & Landmesser, 1996). During the critical period of the visual system, the removal of PSA-NCAM has been shown to regulate the maturation of synapses from parvalbumin (PV) interneurons onto the soma of pyramidal cells in the visual cortex, accelerating the onset of the critical period (Di Cristo et al., 2007).

OXT2

Adding more evidence on the key role of PV interneurons, the transcription factor OXT2 controls the start of the critical period and the maturation of the PV interneurons (Sugiyama et al., 2008). Its absence prevents the opening of critical period plasticity, which can then be triggered by exogenous OTX2 supplement. Remarkably, even though OTX2 is a canonical transcription factor, it can be secreted by the cells expressing it and taken up trans-synaptically; indeed, OTX2 injected into the retina gets transported to the PV interneurons of the visual cortex (Sugiyama et al., 2008). Interestingly, the binding of OTX2 to PV interneurons is mediated by another component of the extracellular matrix, the perineuronal nets (Beurdeley et al., 2012; H. Lee et al., 2017), as we will discuss in the second part of this chapter, since it has been studied as a method to reopen critical period plasticity.

tPA

Another molecule involved in the biology of critical period plasticity is the tissue plasminogen activator (tPA). This molecule is a serine protease expressed throughout the brain, shown to be a regulator of extracellular proteolytic activity (Almonte & Sweatt, 2011). The enzymatic activity of tPA is regulated developmentally: monocular deprivation leads to an increased activity during the naturally occurring critical period in the visual system, but not during adulthood (Mataga, Nagai, & Hensch, 2002).

It appears that tPA activity is necessary for the critical period to open, since tPA KO mice showed no ocular plasticity during the critical period (Mataga et al., 2002). However, in GAD65 KO mice, an animal model with extended plasticity throughout life, monocular deprivation during the critical period does not produce an increase in tPA activity (Mataga et al., 2002), suggesting that GAD65 modulation is required for MD to produce changes in tPA activity.

It has also been shown that in the visual cortex, tPA affects the motility of dendritic spines of pyramidal neurons much like monocular deprivation does (Oray, Majewska, & Sur, 2004). Since the transcription and secretion of tPA are regulated by the neurotrophin brain-derived neurotrophic factor (BDNF) (Fiumelli, Jabaudon, & Magistretti, 1999; Gualandris, Jones, & Strickland, 1996), it has been suggested that the action of tPA on visual plasticity might be controlled by BDNF (Oray et al., 2004). On the other hand, tPA in turn can regulate BDNF function, since the precursor proBDNF can be cleaved into its mature form by plasmin that is activated by tPA (Lee, Kermani, Teng, & Hempstead, 2001; Pang et al., 2004).

Myelin

Myelin is a major inhibitory factor of axonal growth in both the peripheral and the central nervous systems (Fields, 2015), where myelination is mediated by the Nogo receptor (NgR), among others (Pernet & Schwab, 2012). It has been shown that in the visual cortex the amount of myelin in layers IV and V is age-dependent and increases after the closure of the critical period (McGee, Yang, Fischer, Daw, & Strittmatter, 2005). NgR KO mice as well as Nogo-A KO mice show shifts in ocular dominance after the closure of the critical period, while control mice do not (McGee et al., 2005). Interestingly, these effects were not mediated by changes in tPA activity, nor in GAD65 or BDNF expression (McGee et al., 2005), suggesting that NgR might function downstream of these molecules, probably at the same level as extracellular matrix components.

Neurotrophins

Several studies have reported that neurotrophins are involved in visual neuroplasticity (McAllister, Katz, & Lo, 1999). In fact, there is an agreement than the infusion of neurotrophins disrupts the specific changes produced by monocular deprivation in the visual cortex circuitry. Nerve growth factor (NGF) infusions in rats prevent the physiological consequences of MD (Berardi et al., 1993; Domenici, Berardi, Carmignoto, Vantini, & Maffei, 1991; Maffei, Berardi, Domenici, Parisi, & Pizzorusso, 1992), although in kittens it is not able to counteract the effects of MD by itself (Galuske, Kim, Castrén, & Singer, 2000). On the other hand, BDNF infusion into the visual cortex in kittens and ferrets disrupts the formation of ocular dominance columns (Cabelli, Hohn, & Shatz, 1995) and reverses the dominance normally produced by MD (Galuske et al., 2000; Galuske, Kim, Castren, Thoenen, & Singer, 1996). However, chemogenetic functional inhibition of the BDNF receptor TrkB in mice does not interfere with ocular dominance plasticity in response to monocular deprivation, but it prevents the recovery of the deprived eye during the critical period (Kaneko, Hanover, England, & Stryker, 2008). Interestingly, in rats it was further shown that the BDNF released in the retina is responsible for the effects of MD on the ocular dominance (Mandolesi et al., 2005).

Transgenic mice with early overexpression of BDNF showed accelerated onset of the critical period and precocious maturation of inhibitory circuits (Hanover, Huang, Tonegawa, & Stryker, 1999; Huang et al., 1999). BDNF null mutant mice die a few days after birth and are therefore not suitable for studying shifts in ocular dominance. Heterozygous BDNF null (BDNF+/–) mice can be studied, and although these animals show reduced BDNF expression in the visual cortex, they do not show any alteration of ocular dominance (Bartoletti et al., 2002). Nevertheless, decrease of BDNF by dark rearing delays the start of visual plasticity (Gianfranceschi et al., 2003), and a disruption in the binding between promoter regions of BDNF exon IV and cAMP response element-binding protein (CREB) results in decreased inhibitory input (Hong, McCord, & Greenberg, 2008), which impairs the critical period plasticity.

In the barrel cortex of mutant mice displaying reduced BDNF and TrkB expression, there is a delay in the segregation of axons coming from the thalamus into the somatosensory cortex (Lush, Ma, & Parada, 2005). The application of both BDNF and NT-3 reversed the effects of lesioning the whiskers during the naturally occurring critical period, although NGF seemed to enhance the effect (Calia, Persico, Baldi, & Keller, 1998).

Serotonin

The serotoninergic system is also known to influence the biology of the visual system. Kittens depleted of serotoninergic input (through 5,7-DHT infusion) in the visual cortex and subjected to monocular deprivation maintained binocular properties, indicating that serotonin is required for ocular dominance plasticity (Gu & Singer, 1995). Interestingly, the infusion of a 5-HT2C antagonist produced similar effects, blocking ocular dominance plasticity (Wang, Gu, & Cynader, 1997), suggesting that the action of this receptor is required for visual plasticity. However, the role of serotonin in the somatosensory critical period plasticity is somewhat puzzling. There is a dispute on whether depletion of serotoninergic input produces a delay in plasticity within the critical period in terms of barrel size after whisker removal (Osterheld-Haas, der Loos, & Hornung, 1994), or only changes in the metabolic representative area in the adult (Turlejski, Djavadian, & Kossut, 1997). Nevertheless, it seems that serotonin plays a role in the development of the somatosensory cortex, since depletion of serotoninergic input from birth resulted in size reduction of all barrels (Bennett-Clarke, Leslie, Lane, & Rhoades, 1994). Enhanced serotonin expression, on the other hand, has dramatic effects on the formation of cortical maps in the somatosensory cortex (Gaspar, Cases, & Maroteaux, 2003). In mice lacking monoamine oxidase A (MAO-A), barrels fail to form during development, and a similar developmental failure is seen in mice chronically treated with MAO inhibitors (Cases et al., 1996). Similar, although less pronounced, effects are produced by early postnatal treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants (Homberg, Schubert, & Gaspar, 2010).

NMDA

Another factor relevant to understand the biology of the critical periods are N-methyl-D-aspartate (NMDA)-type glutamate receptors. In fact, it has been shown that serotonin facilitates NMDA activity in in vitro models (Nedergaard, Engberg, & Flatman, 1987; Reynolds, Baskys, & Carlen, 1988). NMDA receptors have been long hypothesized to have a role in the critical period plasticity underlying the shifts of ocular dominance, and in kittens it was shown that the infusion of the NMDA receptor antagonist APV (R-2-amino-5-phosphonopentanoate) in combination with monocular deprivation leads to a disruption in the shift of ocular dominance (Kleinschmidt, Bear, & Singer, 1987). Furthermore, the same antagonist was shown to maintain the binocular properties of most responsive cells (Bear, Kleinschmidt, Gu, & Singer, 1990).

More recent studies have shown that the shortening of NMDA currents is disrupted in dark-reared animals (Carmignoto & Vicini, 1992). This shortening of NMDA happens through a switch from NR2B- to NR2A-containing receptors, which can be triggered by a short light exposure in dark-reared animals (Quinlan, Philpot, Huganir, & Bear, 1999). In fact, the balance in receptor subunit composition is affected at different time scales: visual experience decreases rapidly, within hours, the NR2B-only containing receptors decreasing NMDA currents, whereas longer periods (days) of visual deprivation are required to increase NMDA current summation (Philpot, Sekhar, Shouval, & Bear, 2001). Interestingly, mice with NR1B knocked out from the excitatory cortical neurons do not show shifts in ocular dominance (Sawtell et al., 2003). All these results suggest that basic synaptic mechanisms in pyramidal neurons are required for visual plasticity.

In the somatosensory cortex, NMDA receptors seem to play a role in the patterning of the barrels (Iwasato et al., 1997, 2000; Li, Erzurumlu, Chen, Jhaveri, & Tonegawa, 1994). NMDA antagonists seem to block plasticity during the critical period (Fox, Schlaggar, Glazewski, & O’Leary, 1996). During the critical period in the barrel cortex, as in the visual system, there is also a similar switch from NR2B to NR2A subunit containing receptors at the end of the critical period (Barth & Malenka, 2001), although NR2A KO mice do not show a prolonged critical period (Lu, Gonzalez, & Crair, 2001).

It is also important to note that NMDA receptors are influenced by neuromodulatory inputs, since both noradrenaline and acetylcholine have been shown to activate NMDA-mediated responses (Bröcher, Artola, & Singer, 1992; Kirkwood, Rozas, Kirkwood, Perez, & Bear, 1999).

Catecholamines

It was demonstrated a long time ago that catecholamines play an important role in the establishment of ocular dominance; depletion of catecholamines by 6-hydroxydopamine (6-OHDA) disrupts visual plasticity (Kasamatsu & Pettigrew, 1976). Special attention was originally paid to noradrenaline (NA), which was shown to restore visual plasticity when infused in the brain after depletion of catecholamines, allowing MD to produce a shift in the ocular dominance (Kasamatsu, Pettigrew, & Ary, 1979). However, this study is in disagreement with experiments in which a combined depletion of NA and acetylcholine was required to block visual plasticity (Bear & Daniels, 1983; Bear & Singer, 1986). However, later studies confirmed that a one-week infusion of NA was sufficient to affect ocular dominance plasticity in normal light conditions, in the absence of monocular deprivation (Kuppermann & Kasamatsu, 1984). Specifically, it seems the β1 and the α2 adrenergic receptors mediate the effects of NA on critical period plasticity in the visual cortex (Kasamatsu & Shirokawa, 1985; Nelson, Schwartz, & Daniels, 1985).

In this same line, a recent study has shown that dopamine-beta-hydroxylase KO mice, lacking NA from birth, display redistributed responses to frequencies in the auditory cortex (Shepard, Liles, Weinshenker, & Liu, 2015), suggesting that NA is necessary for the critical period plasticity in this region as well.

These results help us understand how the treatment with levodopa, a precursor of dopamine and other catecholamines, has shown promising results as a treatment for amblyopia in children. Levodopa was first isolated from seedlings of Vicia faba, which has been known to improve symptoms of Parkinson’s disease (PD) from the early 1960s (Hornykiewicz, 2010). These effects are mediated through the increased dopamine levels on striatal neurons that in PD are denervated from dopaminergic input (Kakkar & Dahiya, 2015). Regarding critical period plasticity, many studies have confirmed the positive effect of levodopa in amblyopia, both in children and in adults (Leguire, Rogers, Bremer, Walson, & McGregor, 1993; Leguire, Walson, Rogers, Bremer, & McGregor, 1995), although there is controversy on whether this improvement remains stable (Dadeya, Vats, & Malik, 2009) or disappears few months after discontinuation of the treatment (Pandey, Chaudhuri, Kumar, Satyabala, & Sharma, 2002) (Table 1).

It is well known that PD patients have disrupted sensory perception and that levodopa ameliorates these symptoms (Gottlob & Stangler-Zuschrott, 1990). In fact, it is well known that dopamine levels affect retinal cells, including amacrine or horizontal cells (Witkovsky, 2004); altogether showing a pharmacological alternative that might extend the length of the original critical period.

Table 1 Pharmacological Manipulations of the Naturally Occurring Critical Period

Name of the drug

Dose

Way of delivery

Species

System

Reference

Outcome

Muscimol

25 mg/kg

Osmotic infusion into the visual cortex (~7 days)

Cats

Visual

(Reiter & Stryker, 1988)

Pharmacological Manipulation of Critical Period Plasticity

Suberoylanilide hydroxamic acid

25 mg/kg

6 days IP injections

Rats

Visual

(Baroncelli et al., 2016)

Pharmacological Manipulation of Critical Period Plasticity

Bicuculline

1 mg/kg

Osmotic pump infusion into visual cortex

Cats

Visual

(Ramoa et al., 1988)

Pharmacological Manipulation of Critical Period Plasticity

Diazepam

1 mg/kg

Infusion into lateral ventricles or into the brain ventricles

Mice

Visual

(Fagiolini & Hensch, 2000), (T. K. Hensch et al., 1998)

Pharmacological Manipulation of Critical Period Plasticity

FG7142 (GABA inverse agonist)

10 mg/kg

Single subcutaneous injection

Rats

Fear

(Kim & Richardson, 2007)

Pharmacological Manipulation of Critical Period Plasticity

Levodopa

0.55 mg/kg

Orally administered during 7 weeks

Humans

Visual

(Leguire et al., 1995)

Pharmacological Manipulation of Critical Period Plasticity

Mesulergine

160 ng/kg

Osmotic minipump into the visual cortex

Kittens

Visual

(Wang et al., 1997)

Pharmacological Manipulation of Critical Period Plasticity

Pharmacological Manipulations to Reopen Critical Period Plasticity in the Adult Brain

It has been generally considered that once critical periods close, they remain closed during adulthood. However, recent findings have provided evidence that several genetic, enzymatic, environmental, and pharmacological manipulations can reopen critical period–like plasticity in the adult rodent, and perhaps also in the adult human brain (Bavelier, Levi, Li, Dan, & Hensch, 2010).

Extracellular Component Manipulation

Closure of critical periods coincides with increased inhibitory control of cortical circuits and maturation of inhibitory interneurons. At the same time, the perineuronal nets (PNN), extracellular matrix components rich in chondroitin sulphate proteoglycans (CSPG), develop to preferentially encase parvalbumin positive interneurons in the cerebral cortex (Brückner et al., 1994, 2000; Köppe, Brückner, Brauer, Härtig, & Bigl, 1997). Extracellular components, including PNNs, are thought to be, like myelin, inhibitory factors for axonal growth or sprouting (Fawcett & Asher, 1999; Fitch & Silver, 1997; Grumet, Friedlander, & Sakurai, 1996; Huebner & Strittmatter, 2009), and their expression increases throughout age, therefore serving as an indicator of circuit maturity (Brückner et al., 1994).

The first treatment that was shown to reactivate juvenile-like plasticity in the adult brain was intracerebral injection of chondroitinase ABC (ChABC), an enzyme degrading CSPG. Maffei and coworkers infused ChABC into the visual cortex of adult rats to digest CSPGs associated with PNNs and demonstrated that this treatment restores critical period–like plasticity in the adult visual cortex and allows monocular deprivation to produce shifts of ocular dominance (Pizzorusso et al., 2002). These findings opened a tantalizing possibility that critical period plasticity could be reopened after closure.

In addition to the CSPGs, PNNs also contain linking proteins such as Ctrl1 or Bral2. A study using Ctrl1 KO mice showed that the lack of this protein alters the composition of CSPGs (specifically affecting the expression of neurocan) and results in a decreased/altered expression of perineuronal nets. Interestingly, these mice retain critical period plasticity in the visual cortex during adulthood, further supporting the importance of extracellular matrix in the critical period plasticity (Carulli et al., 2010).

PSA-NCAM expression levels are very high during early phases of development, and they decrease as circuits mature (Rutishauser & Landmesser, 1996). Therefore, an increased expression of PSA-NCAM has been associated with more immature states (Ohira, Takeuchi, Iwanaga, & Miyakawa, 2013), resembling a developmental critical period. Interestingly PSA-NCAM expression in the adult brain is mainly found in calbindin-somatostatin expressing interneurons (Gómez-Climent et al., 2011; Guirado, Perez-Rando, Sanchez-Matarredona, Castillo-Gómez, et al., 2014). However, it seems that PSA-NCAM removal also affects the parvalbumin interneuronal subpopulation (Castillo-Gómez, Varea, Blasco-Ibáñez, Crespo, & Nacher, 2011) that regulates the onset of the naturally occurring critical periods as discussed before (Di Cristo et al., 2007). However, removal of PSA-NCAM in the adult brain does not produce a reopening of critical period plasticity (Guirado et al., 2016).

Antidepressants

Probably the most widely used class of drugs that have been shown to trigger brain plasticity during the adulthood is the antidepressants. The first antidepressant drugs, developed 50 years ago, were soon associated with increased levels of serotonin and NA (Bunney & Davis, 1965; Coppen, 1967; Schildkraut, 1965). However, the next generation of antidepressant drugs, including fluoxetine, more specifically inhibit the reuptake of monoamines from the synaptic cleft, allowing enhanced effects of monoamines on the synapsis. Subsequently, it was shown that these antidepressant drugs also increase the expression and signaling of neurotrophic factors such as BDNF (Nibuya, Morinobu, & Duman, 1995; Russo-Neustadt, Beard, Huang, & Cotman, 2000; Saarelainen et al., 2003).

In a landmark study, Maya-Vetencourt et al. demonstrated that chronic treatment with the antidepressant fluoxetine was able to reactivate critical period–like plasticity in the adult visual cortex, allowing the recovery of visual acuity of an amblyopic eye in adult rats (Maya-Vetencourt et al., 2008) (Table 2). Reactivation of juvenile-like plasticity by fluoxetine has subsequently also been observed in mice (Guirado et al., 2016; Steinzeig, Molotkov, & Castrén, 2017). These findings made fluoxetine the first orally administered drug that could reactivate critical period–like plasticity in the adult cortex. Fluoxetine had previously been shown to produce reorganization of axon terminals in the visual pathways of the intact eye in retinal lesion models (Bastos, Marcelino, Amaral, & Serfaty, 1999). Other studies had also demonstrated that this antidepressant could trigger different forms of adult brain plasticity, including hippocampal neurogenesis (Castrén & Hen, 2013; Hajszan, MacLusky, & Leranth, 2005; Malberg, Eisch, Nestler, & Duman, 2000; Sairanen, O’Leary, Knuuttila, & Castrén, 2007).

Table 2 Pharmacological Manipulations of the Critical Period During Adulthood

Name of the drug

Dose

Way of delivery

Species

System

Reference

Outcome

Valproic acid

300 mg/kg

25 days IP injection

Rats

Visual

(Silingardi et al., 2010)

Pharmacological Manipulation of Critical Period Plasticity

250 mg tablets

15 days orally administered (4/day)

Humans

Auditory

(Gervain et al., 2013)

Pharmacological Manipulation of Critical Period Plasticity

100 mg/kg

Single IP injection

Mice

Fear

(Bredy et al., 2007)

Pharmacological Manipulation of Critical Period Plasticity

Sodium butyrate

1.2 g/kg

25 days IP injection

Rats

Visual

(Silingardi et al., 2010)

Pharmacological Manipulation of Critical Period Plasticity

1 g/kg

Single IP injection

Mice

Fear

(Bredy et al., 2007)

Pharmacological Manipulation of Critical Period Plasticity

1.2 g/kg

Single IP injection or cannula infusion into prefrontal cortex

Mice

Fear

(Stafford et al., 2012)

Pharmacological Manipulation of Critical Period Plasticity

Bicuculline

0.06 mg/kg

Acute intravenous injection

Cats

Visual

(Duffy et al., 1976)

Pharmacological Manipulation of Critical Period Plasticity

Diazepam

1 mg/kg

Osmotic minipump infusion into the visual cortex

Mice

Visual

(Fagiolini & Hensch, 2000)

Pharmacological Manipulation of Critical Period Plasticity

2 mg/kg

Osmotic minipump infusion into the visual cortex

Mice

Visual

(Morishita et al., 2010)

Pharmacological Manipulation of Critical Period Plasticity

Citicoline

1000 mg injection

15 days of intramuscular injections

Humans

Visual

(Campos et al., 1995)

Pharmacological Manipulation of Critical Period Plasticity

Droxidopa

300 mg/kg

Orally administered

Cats

Visual

(Mataga et al., 1992)

Pharmacological Manipulation of Critical Period Plasticity

Levodopa

200 mg tablets

Once orally administered

Humans

Visual

(Gottlob & Stangler-Zuschrott, 1990)

Pharmacological Manipulation of Critical Period Plasticity

Physostigmine

0.1 mg/kg

15 days of IP injections

Mice

Visual

(Morishita et al., 2010)

Pharmacological Manipulation of Critical Period Plasticity

FR194921

32 mg/kg

Daily IP injections for 5–9 days

Mice

Auditory

(Blundon et al., 2017)

Pharmacological Manipulation of Critical Period Plasticity

Fluoxetine

10 mg/kg

Orally administered for 4 weeks

Mice

Fear

(Karpova et al., 2011)

Pharmacological Manipulation of Critical Period Plasticity

20 mg/kg

Orally administered for 3 weeks

Rats

Visual

(Maya-Vetencourt et al., 2008)

Pharmacological Manipulation of Critical Period Plasticity

Fluoxetine treatment was shown to increase BDNF expression in the visual cortex. As discussed previously, neurotrophic factors have been shown to play an important role in the neuroplasticity of the visual cortex during development. In the adult visual cortex, BDNF infusion is sufficient to reopen critical period plasticity, and inhibition of BDNF signaling blocks the effects of fluoxetine, again indicating a critical role for BDNF in adult plasticity (Maya-Vetencourt et al., 2008). In addition, infusion of NGF into the adult brain has been shown to reopen critical period plasticity, allowing monocular deprivation to produce shifts in ocular dominance (Galuske et al., 2000; Gu, Liu, & Cynader, 1994). However, BDNF infusion does not appear to affect the ocular dominance plasticity in adult cats (Hata et al., 2000).

It has been suggested that critical period plasticity occurs during adulthood due to a disruption of the excitatory/inhibitory balance. BDNF is one of the key molecules through which neuronal activity regulates inhibitory input to return to this homeostatic equilibrium (Mizuno, Carnahan, & Nawa, 1994; Ohba et al., 2005; Rutherford, DeWan, Lauer, & Turrigiano, 1997), thus BDNF would be a critical molecule to link the plastic changes that occur in the brain with the excitatory-inhibitory balance.

Fluoxetine also reduced extracellular levels of GABA in the visual cortex, and its effects on ocular dominance plasticity can be prevented by benzodiazepine treatment (Maya-Vetencourt et al., 2008). This reduction in the GABAergic transmission promoted by fluoxetine is also reflected at the structural level of cortical interneurons of the visual cortex, where fluoxetine has been shown to promote branch tip dynamics (Chen et al., 2011). In fact, fluoxetine is well known to produce plastic changes in throughout the brain, including interneurons in the medial prefrontal cortex (mPFC) (Guirado, Perez-Rando, Sanchez-Matarredona, Castrén, & Nacher, 2014) and pyramidal neurons in the hippocampus (Hajszan et al., 2005).

In this line, and in addition to the visual system, chronic treatment with fluoxetine also facilitates extinction of fear memories, abolishing the fear response of the renewal phase (Karpova et al., 2011), and ameliorates isolation-induced aggression when fluoxetine treatment is combined with social rehabilitation in rats (Mikics et al., 2017). Interestingly, the effects of fluoxetine were associated with BDNF and TrkB signaling, a decrease in the number of parvalbumin interneurons surrounded by PNNs, and with an increased expression of PSA-NCAM (Karpova et al., 2011; Mikics et al., 2017).

It is important to note that critical period–like plasticity that takes place in the visual cortex after fluoxetine treatment shares many of the characteristics with the plasticity found in rats raised in an enriched environment (EE): BDNF levels are increased and extracellular GABA levels are reduced with both manipulations, and infusion of benzodiazepines can block plasticity induced by both approaches. Future experiments will determine whether these two treatments share a common mechanism of action and whether plasticity induced by one may occlude any plasticity induced by the other treatment.

HDAC Inhibitors

The role of epigenetic regulation of gene expression has recently been a focus in the biology of critical periods. According to their structure and function, four major classes of histone deacetylases (HDAC) have been defined (Kazantsev & Thompson, 2008). Nevertheless, most of the HDACs involved with neuronal plasticity belong to the zinc-dependent classes I and IIa, since HDAC2 and 5 are especially sensitive to both stress and antidepressants, well-known modulators of brain plasticity (Fuchikami et al., 2016). Similarly, studies in human patients have shown involvement of HDAC2 and HDAC5 in depression (Hobara et al., 2010), and HDACs 1, 3, and 4 in bipolar disorder in correlation with changes in expression of plasticity-related molecules such as Reelin and Gad67 (Sharma, Ottenhof, Rzeczkowska, & Niles, 2008), suggesting these class I and II HDACs are the most relevant to critical period biology.

HDAC inhibitors, such as trichostatin-A, acting through class I and II HDACs, have been shown to promote visual plasticity through transcription of different molecules such as CREB (Putignano et al., 2007) and BDNF (Maya-Vetencourt, Tiraboschi, Spolidoro, Castrén, & Maffei, 2011).

Exposure to enriched environment, a non-pharmacological manipulation involved in critical period plasticity, has been shown to reopen critical period plasticity paralleled by an upregulation of histone H3 acetylation (Baroncelli et al., 2016). Similarly, another HDAC inhibitor, sodium butyrate, has also been shown to modulate critical periods in the fear system through BDNF transcription (Bredy et al., 2007) (Table 2), as well as through other mechanisms, such as neuronal nitric oxide synthase (nNOS) (Itzhak, Anderson, Kelley, & Petkov, 2012) or the hippocampal-prefrontal cortex connectivity (Stafford, Raybuck, Ryabinin, & Lattal, 2012).

Valproic acid has received attention recently as a pharmacological approach to reopen critical period plasticity (Table 2). Although it is a widely used antiepileptic drug, the exact mechanism of its action remains poorly understood; nevertheless, it has been shown to alter phosphatidylinositol trisphosphate (PIP3), which is involved in the downstream signaling of protein kinase B (AKT), and to increase GABA levels (Löscher, 1999). Interestingly this drug has recently been classified as an HDAC inhibitor (Göttlicher et al., 2001). In line with this, epigenetic changes produced by valproic acid affect the expression of key molecules regulating critical period plasticity, including BDNF, GAD67, and Reelin (Rodrigo, Ibrahim, & Zarate, 2011). Valproic acid induces reopening of critical period plasticity in the visual system of adult rodent brain (Silingardi, Scali, Belluomini, & Pizzorusso, 2010) as well as in the fear extinction network (Bredy et al., 2007). Moreover, in normal human subjects, it has been shown to promote pitch recognition (Gervain et al., 2013), a property that develops through a critical period in the auditory system (Russo, Windell, & Cuddy, 2003).

Interestingly, other epigenetic mechanisms, such as the genetic deletion of HDAC2 in the GABAergic subpopulation of parvalbumin interneurons, have been shown to decrease inhibition in the adult brain, and enhance long-term depression in layers II/III, a feature of the critical period in the visual cortex, thereby reopening critical period plasticity in the adult brain (Nott, Cho, Seo, & Tsai, 2015).

Cortical Inhibition and Drugs Acting on GABA

As described before, GABAergic neurotransmission influences the timing of the naturally occurring critical periods during development, and increased inhibition is considered a critical component driving the onset as well as closure of critical periods. Recent findings have shown that treatments that reopen critical period plasticity in the adult brain, such as fluoxetine, enriched environment, or insulin-like growth factor-1(IGF-1) infusion (Maya-Vetencourt et al., 2012; Sale et al., 2007), decrease extracellular GABA levels. This has led to the idea that there is a range of inhibition that allows critical period plasticity, higher than the pre-critical period levels but lower than in the adult brain (Sale et al., 2010). In this line, drugs decreasing GABA levels such as the antagonist of GABAA receptor bicuculline have been shown to reopen critical period plasticity in the adult cat brain (Duffy, Burchfiel, & Conway, 1976). On the other hand, benzodiazepines that enhance the effects of GABA on GABAA receptors have been shown to close the permanently open ocular dominance plasticity of mice lacking GAD65 gene expression (Fagiolini & Hensch, 2000; T. K. Hensch et al., 1998; Morishita, Miwa, Heintz, & Hensch, 2010) (Table 2).

Specifically, as discussed, it seems the parvalbumin interneuronal subpopulation plays an important role in triggering critical period plasticity. Interestingly, pharmacogenetic inactivation of PV interneurons has been shown to reopen critical period plasticity in older animals (Kuhlman et al., 2013). It has also been shown that transplantation of GABAergic precursors from the medial ganglionic eminence, maturing into parvalbumin and somatostatin interneurons, can also open a new time-window of visual plasticity in the adult brain (Southwell, Froemke, Alvarez-Buylla, Stryker, & Gandhi, 2010; Tang, Stryker, Arturo, & Espinosa, 2014). Furthermore, as discussed, several extracellular matrix components important for critical period plasticity such as the PNNs or PSA-NCAM are mainly expressed in these subpopulations of interneurons in the adult brain (Brückner et al., 1994; Gómez-Climent et al., 2011).

Citicoline

Very little is known about the role of lipids in critical period plasticity. Citicoline is a molecule involved in the synthesis of phospholipids (Kennedy & Weiss, 1956), especially as an intermediate compound in the synthesis of phosphatidylcholine from choline (Kent & Carman, 1999). Although the mechanism of action of citicoline is not well understood in regard to brain plasticity, citicoline has been involved with several signaling cascades related with neuronal plasticity (Bazan, 2005). Through molecules such as the platelet-activating factor or the phospholipase A2, it induces metalloprotease gene expression, long-term potentiation (LTP), and learning and memory (Adibhatla & Hatcher, 2002). Nevertheless, the effects of citicoline have been extensively studied after ischemia (Adibhatla & Hatcher, 2002; Grieb, 2014). Citicoline has been hypothesized to provide a neuroprotective effect by increasing the synthesis of phospholipids, which are decreased after ischemia as they are catabolized from the neuronal cell membranes (Weiss, 1995). Similarly, it has been hypothesized that citicoline restores the activity of mitochondrial membrane ATPase by improving membrane stability (Secades, 2011).

Since choline is a substrate for both phospholipids and acetylcholine synthesis, certain conditions increasing the demand for acetylcholine, such as ischemia, deplete choline and trigger the catabolism of phospholipids to obtain choline (Overgaard, 2014). By improving the availability of choline, citicoline not only increases the levels of acetylcholine (Giménez, Raïch, & Aguilar, 1991), but also interacts with other neurotransmitter systems increasing dopamine and NA (Blusztajn & Wurtman, 1983; Martinet, Fonlupt, & Pacheco, 1979). These mechanisms might explain how chronic treatment with citicoline ameliorates amblyopia in human patients, increasing the visual acuity not only in the lazy eye but also in the dominant eye (Campos, Schiavi, Benedetti, Bolzani, & Porciatti, 1995) (Table 2).

Catecholamines

As we have discussed, NA was one of the first ascending neuromodulatory systems shown to be involved in the biology of critical period plasticity (Kasamatsu et al., 1979). In this line, electrical stimulation of the locus coeruleus—the main source of noradrenergic input in the brain—in adult animals or infusion of NA into the visual cortex allowed monocular deprivation to produce changes in ocular dominance (Kasamatsu, Watabe, Heggelund, & Schöller, 1985; Kuppermann & Kasamatsu, 1984). In fact, electrical stimulation in the locus coeruleus has also been shown to promote specific frequency selective changes, a form of auditory plasticity (Edeline, Manunta, & Hennevin, 2011). On the other hand, the depletion of NA in the somatosensory cortex blocks the expansion of the metabolic area in the barrel cortex that normally occurs after trimming of the neighboring whiskers (Levin, Craik, & Hand, 1988).

Droxidopa, a precursor of NA able to pass the blood–brain barrier, is a pharmacological approach to manipulate NA levels in the brain. In the cat brain, through microdialysis, it has been shown to effectively increase the levels of NA in the visual cortex and to promote a shift in the ocular dominance in the adult brain (Mataga, Imamura, & Watanabe, 1992) (Table 2). One suggested possible mechanism through which droxidopa could reopen critical period plasticity is through tPA, since droxidopa has been shown to induce an increase of tPA mRNA expression in the visual cortex (Mataga et al., 1996).

Based on these results, Gottlob and Zuschrott found that levodopa, another catecholamine precursor, increases contrast sensitivity in the non-dominant eye, leaving the dominant eye intact, and therefore ameliorates amblyopia (Gottlob & Stangler-Zuschrott, 1990). An animal study has suggested that one of the factors involved in levodopa-mediated reopening of critical periods is the NMDA receptor subunit 1, which is upregulated after levodopa treatment (Sun & Zhang, 2012).

Cholinergic System

Another neuromodulatory input related to the biology of critical periods is acetylcholine. There is evidence that acetylcholine might influence plasticity in the adult somatosensory system. Each part of the body has a representation in the somatosensory cortex (Penfield & Boldrey, 1937), and, for example, amputation of a finger leads to the shrinkage of the area responding for the lost limb and an expansion of the neighboring areas (Flor et al., 1995). However, lesions causing depletion of cholinergic transmission block this expansion of the neighboring areas, both in cats (Juliano, Ma, & Eslin, 1991) and rats (Webster, Hanisch, Dykes, & Biesold, 1991).

More support for the role of cholinergic transmission in the critical period plasticity comes from the fact that nicotinic acetylcholine receptors (nAChR) bind to Lynx1, a neurotoxin-like molecule expressed in large projecting pyramidal neurons (Miwa et al., 1999). Through changes in the receptor subunit stoichiometry of nAChR, lynx1 is thought to modulate cholinergic transmission (Nichols et al., 2014). In line with this, Lynx1 null mutant mice exhibit enhanced synaptic efficacy at the electrophysiological level and enhanced learning and memory behavioral tests, but it also leads to neurodegeneration (Miwa et al., 2006).

Expression of Lynx1 increases towards the end of visual critical period—after P28—(Morishita et al., 2010) and it might be part of the mechanism for the closure of the critical period. In this line, lynx1 KO mice maintain an open critical period throughout adulthood (Morishita et al., 2010). Interestingly, in lynx1 KO mice, MD produced an increase of tPA activity in the visual cortex of adult mice (Bukhari et al., 2015), suggesting that the remodeling of extracellular matrix degradation may play a role mediating the critical period plasticity triggered by removal of Lynx1.

These results open the possibility that pharmacological manipulation of the cholinergic system might regulate critical period plasticity. Inhibition of the acetylcholinesterase enzyme by acetylcholinesterase inhibitors (AChEi) diminishes acetylcholine breakdown and produces higher synaptic levels of this neurotransmitter. One of the first AChEis developed for clinical use was physostigmine, a drug studied in modern medicine by Thomas Fraser as an atropine antagonist (Scheindlin, 2010). Second-generation AChEis with fewer side effects, such as donepezil, have been used during the last 20 years as a first-line pharmacological treatment for Alzheimer’s disease, mainly due to an improvement in cognitive function after using these drugs (Bullock & Dengiz, 2005). Moreover, it has been shown that AChEis also improve sensory perception (Bentley, Husain, & Dolan, 2004; Ricciardi, Handjaras, Bernardi, Pietrini, & Furey, 2013), supporting a general role for AChEi of increasing the signal-to-noise ratio in sensory perception in healthy patients also (Rokem & Silver, 2010).

In rodents, AChEi have also been shown to improve sensory perception and signal-to-noise ratio (Soma, Suematsu, & Shimegi, 2013). This might be the underlying mechanism through which physostigmine can restore plasticity in the visual cortex, allowing shifts of ocular dominance in adult wildtype (Morishita et al., 2010) (Table 2). Based on these findings, donepezil, another acetylcholinesterase inhibitor, is now being tested in clinical trials to prove its efficiency for amblyopia in adult humans (clinical trial NCT01584076).

Adenosine

As discussed, it has been suggested that restoring long-term synaptic plasticity through changes in NMDA receptors in the thalamic afferents is responsible for the critical period plasticity (Crair & Malenka, 1995). Interestingly, by modulating cholinergic transmission, this synaptic plasticity can be restored, therefore reopening critical period plasticity in the adult brain (Blundon, Bayazitov, & Zakharenko, 2011; Chun, Bayazitov, Blundon, & Zakharenko, 2013). In this line, it has been recently shown that this reopening of critical period plasticity in the adult auditory cortex is mediated by adenosine receptor signaling. Treating mice with the selective A1R antagonist FR194921 is sufficient to reopen such auditory critical period plasticity, allowing pairing tone exposure to reshape auditory cortical maps (Blundon et al., 2017). In line with this, caffeine, which has been shown to act, in low doses, as an antagonist for adenosine receptors including A1R (Fredholm, Yang, & Wang, 2017), might reopen or extend critical period plasticity. This idea is currently being tested in a study of the ability of caffeine to improve amblyopia in children a few years after the closure of the critical period in the visual system (clinical trial NCT02594358).

Acknowledgments

The original research in our laboratory has been supported by the European Research Council grant No. 322742—iPLASTICITY, the Sigrid Jusélius Foundation, EU Joint Programme—Neurodegenerative Disease Research (JPND) project # JPCOFUND_FP-829-007, HiLife Fellows program and Academy of Finland grants #294710, #303124, and #307416.

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