Early-onset generalized torsion dystonia (DYT1) is an autosomal dominant movement disorder, commonly caused by a GAG base-pair deletion in the TOR1A gene coding for torsinA protein, without gross brain structural defects or other detectable neuropathology (Ozelius et al., 1997; Ledoux et al., 2013). Intriguingly, only 30–40% of DYT1 mutation carriers develop dystonia, typically in childhood-early adolescence (Bressman et al., 2000). However, what triggers the clinical onset of symptoms is currently unknown, although the presence of a critical developmental period of susceptibility is highly probable, since mutation carriers that do not develop symptoms in that time-window remain unaffected for their entire life (Pappas et al., 2014).

Plasticity changes include functional and structural synaptic specialization, leading to experience-dependent acquisition of motor skills. However, genetic or acquired alterations may lead to maladaptive plasticity changes. Accordingly, human studies indicate neural processing and synaptic plasticity alterations as major determinants in dystonia pathophysiology (Quartarone and Hallett, 2013). A significantly enhanced responsiveness to plasticity protocols has been reported in dystonic patients (Edwards et al., 2006; Weise et al., 2006; Quartarone et al., 2009). Moreover, patterns of impaired motor learning have been described even in clinically unaffected DYT1 mutation carriers (Ghilardi et al., 2003), further supporting the notion that aberrant plasticity represents a unique endophenotype in dystonia.

Of note, an impairment of striatal plasticity has been demonstrated in a number of different DYT1 models, including transgenic mice and rats overexpressing mutant torsinA (Martella et al., 2009; Grundmann et al., 2012), knock-in mice heterozygous for Δgag-torsinA (Dang et al., 2012; Martella et al., 2014; Rittiner et al., 2016), revealing an impressive similarity with studies of synaptic plasticity in human dystonia. Collectively, these observations support the hypothesis that DYT1 dystonia is a complex neurodevelopmental disorder of abnormal neurochemistry, wiring, and physiology (Goodchild et al., 2013; Pappas et al., 2014).

However, these alterations were observed in adult rodents, and to date, a relationship between age and corticostriatal plasticity in dystonia is still lacking. Furthermore, the question as to whether functional and structural plasticity abnormalities occur early in life or later as adaptive changes remains unknown. We report structural and functional abnormalities occurring in a defined postnatal time-window in Tor1a^+/Δgag mice, indicative of a ‘premature’ and abnormal functional and structural plasticity, which is paralleled by a time-dependent increase in both BDNF levels and AMPAR-mediated currents.

Our findings reveal molecular, functional and structural changes in DYT1 striatal spiny projection neurons (SPNs), emphasizing the link between abnormal plasticity and dystonia. Understanding the key stages at which synaptic circuits are affected could suggest new routes to prevent or treat the disorder.

The critical period for symptom onset in DYT1 dystonia matches a time-window of postnatal life when motor memories are shaped by activity-dependent changes in the striatum. Thus, in order to characterize plasticity changes in the early adolescence, Tor1a^+/Δgag mice were recorded from postnatal day P15 to P35, in good agreement with the approximate life phase equivalencies between humans and mice, predicting that ~4 weeks of mouse age correspond to ~14 years in humans (Flurkey et al., 2007).

Electrophysiological characterization of SPNs

Properties of adult Tor1a^+/Δgag SPNs have been extensively characterized (Maltese et al., 2014; Martella et al., 2014). Here, we focused on intrinsic and synaptic properties of juvenile Tor1a^+/Δgag neurons. SPNs recorded at P26 from both Tor1a^+/+ and Tor1a^+/Δgag mice did not display firing activity at rest and exhibited no significant differences in their intrinsic membrane properties (data not shown). Depolarizing and hyperpolarizing current steps caused tonic action potential discharge and strong inward membrane rectification (Figure 1A). Short ISI (25–50 ms) of paired synaptic stimulation induced PPF in both genotypes (Figure 1B; p<0.05). At longer ISI (100–1000 ms), PPF was not observed in juvenile Tor1a^+/+ and Tor1a^+/Δgag mice (Figure 1B; p>0.05). To explore potential differences in neurotransmitter release, we recorded spontaneous glutamate- and GABA-mediated currents in P26 SPNs from both Tor1a^+/+ and Tor1a^+/Δgag mice. Glutamatergic sEPSCs did not differ between genotypes (Figure 1C; p>0.05). However, we found a significant increase in the amplitude, but not in the frequency, of mEPSCs recorded from Tor1a^+/Δgag mice compared to wild types (Figure 1D; p<0.05). Conversely, GABAergic sIPSCs were unchanged in Tor1a^+/Δgag with respect to Tor1a^+/+ littermates (Figure 1E; p>0.05). Also, mIPSCs were similar in both genotypes (Figure 1F; p>0.05).

Figure 1

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Electrophysiological and synaptic properties of striatal SPNs.

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Premature expression of corticostriatal synaptic plasticity

We previously demonstrated a marked impairment of bidirectional synaptic plasticity in adult (P60-P75) Tor1a^+/Δgag striatum (Martella et al., 2014). However, it remains unclear whether these patterns of abnormal plasticity are core pathologic features in an early developmental period, or occur later as maladaptive changes. Thus, we performed a detailed characterization of LTD and LTP from P15 to P35 in Tor1a^+/+ and Tor1a^+/Δgag mice. In Tor1a^+/+ SPNs, HFS failed to induce LTD from P15 to P27 (Figure 2A; p>0.05). Conversely, the HFS protocol elicited a robust LTD from P28 to P35 (Figure 2A; 59.63 ± 2.63% of control; p<0.05). Surprisingly, in slices from Tor1a^+/Δgag mice, HFS stimulation failed to cause a synaptic depression, independently from the postnatal day of recording (Figure 2B; p>0.05).

Figure 2

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Altered developmental profile of corticostriatal long-term synaptic plasticity expression in Tor1a^+/Δgag mice.

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The LTP induction protocol failed to elicit a potentiation in Tor1a^+/+ mice from P15 to P23 (Partridge et al., 2000) (Figure 2C; p>0.05), whereas a stable LTP occurred from P24 to P35 (Figure 2C; 148.80 ± 15.39% of control; p<0.05). Unexpectedly, in Tor1a^+/Δgag SPNs LTP could be evoked as early as P15, revealing a premature onset, and showed a tendency to increase, compared to wild types (Figure 2D; Tor1a^+/Δgag P15-23, 174.68 ± 22.59% of control; P24-35, 172.35 ± 11.06% of control; p<0.05).

The pattern of torsinA expression is common to all striatal DARPP-32-labeled neurons (Martella et al., 2009). To unmask potential differences between direct- and indirect-pathway SPNs, recording electrodes were filled with biocytin. Enkephalin staining revealed that neither ENK-positive nor ENK-negative SPNs exhibited LTD, ruling out a possible segregation to a specific population of SPNs (Figure 2E).

Collectively, these data demonstrate that LTD appeared at P28 in wild-type mice, whereas it could not be elicited during the entire postnatal period of observation in Tor1a^+/Δgag mice (Figure 2E). Moreover, while in Tor1a^+/+ mice LTP could not be evoked before P24, in SPNs from Tor1a^+/Δgag LTP appeared prematurely at P15 (Figure 2F).

Increased AMPA receptor function and abundance at corticostriatal synapses during development

Changes in synaptic strength during learning and memory processes implicate an accurate regulation of AMPARs and NMDARs expression at postsynaptic membranes (Bassani et al., 2013; Czöndör and Thoumine, 2013). Thus, we performed an electrophysiological and biochemical characterization of AMPARs and NMDARs of SPNs in both Tor1a^+/+ and Tor1a^+/Δgag mice.

To investigate the relative abundance of postsynaptic AMPARs and NMDARs, NMDAR/AMPAR current ratios at corticostriatal synapses were evaluated in both juvenile (P26) and adult (P60) Tor1a^+/+ and Tor1a^+/Δgag SPNs (Figure 3A–B). We found that, at P26, the NMDAR/AMPAR ratio was significantly reduced in Tor1a^+/Δgag SPNs compared to wild types (Figure 3A; p<0.05). Conversely, no significant differences were recorded in P60 SPNs of both genotypes (Figure 3B; p>0.05). A reduced NMDAR/AMPAR ratio could reflect an increase in AMPAR function or number, a decrease in NMDARs function, or even a combination of both. To detect possible differences in the composition of postsynaptic glutamate receptors in P26 SPNs, a IV relationship of AMPAR-EPSC was recorded (Figure 3C). Tor1a^+/Δgag SPNs showed a significantly increased current at hyperpolarized voltage ranges (Figure 3C; 2-way ANOVA, p<0.01;HP= −70 mV). The GluA2 subunit reduces AMPAR permeability to Ca²⁺. Therefore, depending on the subunit composition, AMPAR-EPSC may show a linear or an inward-rectifying IV relationship (Cull-Candy et al., 2006). Thus, we measured the rectification index (RI), calculated as the ratio between the AMPAR-EPSC at −70 mV and at +40 mV (Isaac et al., 2007). We observed no significant difference in RI between genotypes (Figure 3C; p>0.05), suggesting that the enhanced AMPAR current involves an increased surface expression of AMPARs, rather than an altered receptor composition. Moreover, the AMPAR-EPSC IV relationship was also recorded in the presence of the selective antagonist of GluA2-lacking AMPARs, NASPM (100 μM). No significant difference in the RI of P26 SPNs was measured in the presence of NASPM (Figure 3D; p>0.05); yet, at hyperpolarized voltage ranges AMPAR-mediated current was still increased in Tor1a^+/Δgag SPNs (Figure 3D; two-way ANOVA, p<0.01 at HP =−70 mV). These results further excluded possible alterations of AMPAR surface composition.

Figure 3

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Electrophysiological characterization of AMPAR and NMDAR currents at corticostriatal synapses of SPNs in both Tor1a^+/+ and Tor1a^+/Δgag mice.

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The normalized IV relationship of NMDAR-EPSCs showed the characteristic ‘J-shape’ (Mayer et al., 1984) in SPNs recorded at P26 from both genotypes (Figure 3E). No significant difference was found in the voltage-dependence of NMDARs (p>0.05). By analyzing the kinetics of the response at HP =+ 40 mV, we detected a significantly decreased decay time in Tor1a^+/Δgag mice compared to controls (Figure 3F,G; p<0.05), despite a comparable rise time, suggesting a modification of NMDAR subunit composition (Paoletti et al., 2013). In particular, it is well-established that the decay time of NMDAR currents is correlated to the amount of GluN2-type subunits. GluN2A and GluN2B represent the most abundant NMDAR regulatory subunits expressed in SPNs (Chen and Reiner, 1996; Dunah and Standaert, 2003) and are characterized by a fast and slow decay time, respectively (Sanz-Clemente et al., 2013).

Taking into account all the above-described electrophysiological results, we evaluated the levels of AMPAR and NMDAR subunits into TIF fractions purified from striata of both juvenile (P26) and adult (P60) mice by means of WB analysis. We found a significant increase in the levels of both GluA1 and GluA2 AMPAR subunits in the postsynaptic compartment of P26 Tor1a^+/Δgag mice compared to controls (Figure 4A,B; p<0.05), consistent with the observed reduction of the NMDA/AMPA ratio and the absence of any alteration of the RI (see Figure 3). Interestingly, we also found an increase of phosphorylation at GluA1-Ser845 (Figure 4A,B;, p<0.05), which is known to be correlated with LTP expression and to prevent endocytosis of GluA1-containing AMPARs (Oh et al., 2006; Bassani et al., 2013). Moreover, in agreement with the reduction of the NMDAR decay time, we observed an increase of GluN2A but not GluN2B subunit at postsynaptic sites of P26 Tor1a^+/Δgag mice compared to Tor1a^+/+ (Figure 4C,D; p<0.05). Finally, no modifications of PSD-95, the most abundant scaffolding protein at the excitatory synapse, was observed (Figure 4C,D). Notably, these alterations of AMPAR and NMDAR subunits were not present in SPNs from P60 Tor1a^+/Δgag mice (Figure 4; p>0.05).

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Next, we performed a detailed evaluation of dendritic spine density and morphology in Tor1a^+/Δgag SPNs, compared to age-matched Tor1a^+/+ mice. P26 Tor1a^+/Δgag SPNs (Figure 5A–D) exhibited a higher number of mushroom-type spines (Figure 5C; p<0.05) and, consequently, a concomitant overall increase of dendritic spine width compared to Tor1a^+/+ mice (Figure 5B; p<0.05), thus suggesting an advanced stage of spine maturation, in agreement with the observed molecular GluN2A/GluN2B switch (see Figure 4). This event was associated, as expected, to an overall decrease of dendritic spine density (Figure 5A; p<0.05).

Figure 5

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Analysis of dendritic spines morphology in P26 Tor1a^+/Δgag compared to age-matched Tor1a^+/+ mice.

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Analysis of dendritic spines morphology in P60 Tor1a^+/Δgag compared to age-matched Tor1a^+/+ mice.

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Conversely, P60 Tor1a^+/Δgag mice (Figure 5E–H) showed a normalization of dendritic spine density (Figure 5E; p>0.05) and of spine width (Figure 5F; p>0.05) compared to Tor1a^+/+ mice. Furthermore, with respect to P26, at P60 the number of mushrooms remained unchanged in Tor1a^+/Δgag mice but increased in Tor1a^+/+ (Figure 5G; p<0.05). Yet, at P60 Tor1a^+/Δgag mice showed an increase of thin spines compared to Tor1a^+/+ mice (Figure 5G; p<0.05).

Increased BDNF protein expression in Tor1a^+/Δgag striatum at P26

Neurotrophic factors play a fundamental role in the development of SPNs and synaptic plasticity maturation (Altar et al., 1997; Rauskolb et al., 2010). Particularly, BDNF contributes to the developmental expression of AMPAR subunits at postsynaptic compartments (Jourdi et al., 2003; Jourdi and Kabbaj, 2013). The majority of BDNF, anterogradely transported to the striatum, originates from the cortex, where its expression begins in the first postnatal days (Baydyuk and Xu, 2014). We first performed a WB time-course analysis of BDNF protein level in P15, P26 and adult (P60-P75) striatum. BDNF expression profile showed a similar age-dependent time-course in both genotypes (Figure 6A,B; P15 vs P26: Tor1a^+/+ p<0.05; Tor1a^+/Δgagp<0.01). As indicated by the BDNF/proBDNF ratio, in line with previous evidence (Zermeño et al., 2009), BDNF was highly expressed at P15 in both strains. At P26 the signal decreased, and then reached intermediate values in adults (Figure 6A,B).

Figure 6

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BDNF protein expression in the striatum of Tor1a^+/+ and Tor1a^+/Δgag mice.

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Next, we compared striatal proBDNF and BDNF protein levels between genotypes at P26. In line with previous evidence, proBDNF was detected as a double band at ~32 KDa, whereas mature BDNF as a single band at 14 KDa (Hartog et al., 2009; Koshimizu et al., 2009; Mandel et al., 2009; Tropea et al., 2011) (Figure 6C). Both proBDNF and BDNF levels were increased at P26 in Tor1a^+/Δgag striatum (Figure 6C; proBDNF p<0.01, BDNF p<0.05). We therefore examined Bdnf mRNA expression in Tor1a^+/Δgag cortex. Quantitative PCR revealed an increased Bdnf expression in Tor1a^+/Δgag cortex as compared to Tor1a^+/+ (Figure 6D; p<0.05). No significant difference between genotypes was measured in the proBDNF and BDNF striatal protein levels in adult mice (Figure 6E; p>0.05). Collectively, these data indicate an increase of BDNF level in P26 Tor1a^+/Δgag striatum.

BDNF regulates surface AMPA receptor expression and synaptic plasticity

BDNF has been shown to contribute to LTP induction in normal mice (Jia et al., 2010). To test whether the increase in BDNF levels was involved in the abnormal regulation of AMPA currents and in the synaptic plasticity deficits, BDNF signalling was selectively blocked by the tropomyosin-related kinase B (TrkB) receptor competitive antagonist, ANA-12 (Cazorla et al., 2011). A single in vivo administration of ANA-12 (0.5 mg/kg, intraperitoneal, 4 hr before the experiment) failed to rescue synaptic plasticity deficits in young Tor1a^+/Δgag mice (data not shown). However, repetitive treatment with ANA-12 (0.5 mg/kg, intraperitoneal, 12 hr and 4 hr before the experiment; Cazorla et al., 2011; Stragier et al., 2015), completely rescued corticostriatal LTD expression in P28-35 Tor1a^+/Δgag mice (Figure 7A; p<0.05). Additionally, ANA-12 treatment reduced LTP amplitude in P24-35 Tor1a^+/Δgag mice (Figure 7B; p>0.05). In vehicle-treated Tor1a^+/+ and Tor1a^+/Δgag mice, no significant change was observed (data not shown).

Figure 7

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In vivo ANA-12 treatment rescues synaptic plasticity deficits in juvenile Tor1a^+/Δgag mice.

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Likewise, in vivo treatment with ANA-12 totally normalized the IV curve of AMPAR-EPSC in P26 Tor1a^+/Δgag mice (Figure 7C; p>0.05). Accordingly, also the RI displayed no significant difference between genotypes (Figure 7C; p>0.05). These findings suggest that increased BDNF levels are involved in the abnormal developmental expression of AMPARs on SPN postsynaptic membranes, leading to synaptic plasticity alterations in juvenile mice.

Finally, to demonstrate that BDNF alterations occur in a defined time-window, we tested the effect of ANA-12 on corticostriatal LTD expression in adult Tor1a^+/Δgag mice. In vivo treatment with ANA-12 (0.5 mg/kg, intraperitoneal, two administrations at 12 hr and 4 hr before the experiment) failed to restore corticostriatal LTD in P60 Tor1a^+/Δgag mice (Figure 7D; p>0.05) confirming that BDNF-dependent alterations are limited to a sensitive period.

The critical period for the onset of symptoms in DYT1 dystonia patients matches an early time-window of activity-dependent plastic changes in the striatum, which shape motor memory and learning processes during childhood and early adolescence.

Our systematic analysis of functional and structural synaptic plasticity in DYT1 dystonia demonstrates: (i) The existence of a critical period when SPNs exhibit premature LTP; (ii) A significant increase of AMPAR levels in the postsynaptic compartment which correlates with the reduction of NMDA/AMPA ratio, the increased amplitudes of postsynaptic currents and the rightward shift in the AMPA I-V curve observed in juvenile Tor1a^+/Δgag mice; (iii) A BDNF time-dependent increase in expression profile, which parallels the alterations described; (iv) abnormal plasticity is associated with profound changes of dendritic spine density and morphology in juvenile Tor1a^+/Δgag; (v) A rescue of the synaptic plasticity deficits is obtained by in vivo administration of a TrkB inhibitor.

It is currently unknown why penetrance is only 30% in DYT1 mutation carriers. One possibility is that at circuit level, motor system is already impaired early during development. The existence of a defined period in which neurons are particularly susceptible to experience-driven modifications is well-established, concurrently with structural modifications, and is currently believed to represent a nodal mechanism both in physiological and pathological conditions (Turrigiano and Nelson, 2004; Johnston, 2004; Meredith, 2015; Calabresi et al., 2016).

Our electrophysiological assessment of synaptic plasticity identifies a rather narrow time-window, between P15 and P26 when striatal SPNs exhibit a premature LTP, whereas LTD cannot be evoked. Although it has to be cautiously reminded that these alterations match those described in adult DYT1 striata (Martella et al., 2014), the time-course performed in the present study indicates their abnormal early appearance, in a developmental phase when normal striatal SPNs do not yet exhibit long-lasting synaptic changes. Of interest, the loss of LTD was observed in a similar time frame in a novel model with a rare missense variant in the Tor1a gene (Bhagat et al., 2016).

Moreover, we describe, along with electrophysiological deficits, molecular and structural changes at striatal synapses that appear to be limited to a specific time-window. Striatal LTP either in mature tissue preparation or in the developing striatum is dependent on the activation of NMDAR (Calabresi et al., 1992b; Partridge et al., 2000), whereas LTD depends on AMPAR (Calabresi et al., 1992a). Our electrophysiological and biochemical characterization demonstrates an increase in currents mediated by AMPAR, consistent with the increased amplitude of mEPSCs, and additionally, the NMDAR/AMPAR ratio was significantly reduced in SPNs from DYT1 mice. A major mechanism regulating synaptic strength involves the balance between synaptic insertion and removal of glutamate receptors into the postsynaptic membrane (Gong and De Camilli, 2008). Specifically, loss of homeostatic regulation of excitatory synapses in distinct neuronal subtypes involve postsynaptic changes in accumulation of AMPAR (Lissin et al., 1998; O'Brien et al., 1998). Accordingly, we observed a significant increase of both GluA1 and GluA2 subunits of AMPARs in the postsynaptic compartment of P26 Tor1a^+/Δgag mice compared to controls, suggestive of an increased surface expression of AMPARs. Of interest, the significant increase of the phosphorylation of GluA1-Ser845, a well-established correlate of LTP (Oh et al., 2006; Bassani et al., 2013) is consistent with the abnormal LTP expression measured in DYT1 mice. Moreover, GluA1-Ser845 (Roche et al., 1996) plays a key role in the synaptic delivery of GluA1-containing AMPARs by LTP (Esteban et al., 2003; Bassani et al., 2013) and is involved in surface reinsertion/stabilization of AMPARs (Ehlers, 2000), thus providing a molecular mechanism for the observed increase of AMPARs at postsynaptic membranes in P26 Tor1a^+/Δgag mice compared to controls. Thus, we hypothesize that the loss of LTD may be related to the aberrant composition of striatal AMPARs observed in mutant mice.

The identification of increased AMPAR subunit levels in the postsynaptic compartment offers new opportunities to identify potential regulators of AMPAR turnover. Neurotrophins have been implicated in glutamatergic synapse development and plasticity, suggesting a potential role in postsynaptic proteins distribution (Causing et al., 1997; McAllister et al., 1997; Kong et al., 2001). Previous work elucidated the role of BDNF in the regulation of AMPAR expression and function, including synaptic AMPAR subunit trafficking (Narisawa-Saito et al., 1999; Jourdi and Kabbaj, 2013). Indeed, BDNF treatment acutely controls both AMPAR subunits and their scaffolding proteins trafficking, thereby modifying the strength of synaptic activity (Minichiello et al., 1999; Mauceri et al., 2004). Remarkably, we observed an enhancement of pro-BDNF and BDNF protein level in P26 Tor1a^+/Δgag mice, which appears critical for the onset of abnormal neurophysiological phenotype in DYT1 dystonia. Consistently, we obtained a functional rescue of synaptic plasticity and AMPA-mediated currents with the competitive antagonist of BDNF TrkB receptor ANA-12 (Cazorla et al., 2011).

Activity-dependent synaptic plasticity as well as composition and activity of NMDARs and AMPARs strictly govern modifications of dendritic spine morphology, leading to a long-lasting structural plasticity. Yet, BDNF also plays a major role in spine maturation in several brain regions, including the striatum (Baquet et al., 2004; Rauskolb et al., 2010). Thus, the abnormal increase in BDNF expression fits with the abnormalities in spine morphology we observed. In P26 Tor1a^+/Δgag mice, we measured an increase in mushroom spines, suggestive of a ‘premature’ maturation process accompanied by an overall decrease in the density of dendritic spines. It is well-known that expression patterns of the GluN2 subunits of NMDARs at dendritic spines change during the first postnatal weeks. In particular, GluN2A expression increases from the second postnatal week to become widely expressed and abundant throughout the brain (Bellone and Nicoll, 2007; Gray et al., 2011). Yet, in agreement with the reduction of the NMDAR decay time, we found an increase of postsynaptic GluN2A in P26 Tor1a^+/Δgag mice suggesting a ‘premature’ GluN2A/GluN2B switch, thus indicating the existence of a molecular and morphological early maturation of the excitatory synapse in this DYT1 model. Moreover, the existence of a close coordination between spine size and AMPAR levels at synaptic membranes has been previously reported (Kopec et al., 2007; Malinverno et al., 2010) and spine volume has been positively correlated with the strength of AMPAR-mediated synaptic transmission. Accordingly, in Tor1a^+/Δgag mice we found a significant increase of spine head width, an increase in mushroom spines and a concomitant increase of both GluA1 and GluA2 subunits of AMPARs.

Most of the molecular and structural alterations described in juvenile DYT1 mice were not confirmed at our analyses performed in adult (P60) mice. Indeed, inhibition of BDNF with ANA-12 did not offset the plasticity deficits in adult mice. Additionally, the anticholinergic agent pirenzepine failed to rescue the plasticity deficits in juvenile animals, contrarily to what reported in adults (Dang et al., 2012; Martella et al., 2014), indicating that distinct mechanisms sustain the abnormal patterns of synaptic activity at different developmental ages. Future work is required to address the precise mechanisms governing this switch.

Collectively, we demonstrate that the rise of BDNF, in a restricted time-window, drives AMPA receptor composition changes and, consequently, structural modifications in spine morphology, resulting in the loss of homeostatic regulation of synaptic plasticity early in postnatal life.

Our hypothesis is also consistent with the clinical observation that the beneficial effects of Deep Brain Stimulation (DBS) in dystonic patients is more effective in young patients, as compared to patients implanted later in life (Isaias et al., 2008). Additionally, compared to the prompt efficacy observed in Parkinson’s disease patients, weeks are commonly required to obtain symptomatic relief following DBS, and improvements may continue to be manifest over time (Vercueil et al., 2001; Krauss, 2002; Vidailhet and Pollak, 2005). It is plausible that severity of abnormal plasticity is related to disease duration, thus justifying the longer time required to erase aberrant plasticity patterns.

In a therapeutic perspective, these sensitive periods might be considered as temporal windows of opportunity, during which specific molecular steps could be targeted to prevent aberrant plasticity to develop.

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Author details

1. Marta Maltese

   1. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
   2. IRCCS Fondazione Santa Lucia, Rome, Italy

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

2. Jennifer Stanic

   Department of Pharmacology, University of Milan, Milan, Italy

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing—original draft

   Competing interests

   No competing interests declared

3. Annalisa Tassone

   1. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
   2. IRCCS Fondazione Santa Lucia, Rome, Italy

   Contribution

   Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

4. Giuseppe Sciamanna

   1. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
   2. IRCCS Fondazione Santa Lucia, Rome, Italy

   Contribution

   Data curation, Supervision, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

5. Giulia Ponterio

   1. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
   2. IRCCS Fondazione Santa Lucia, Rome, Italy

   Contribution

   Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

6. Valentina Vanni

   1. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
   2. IRCCS Fondazione Santa Lucia, Rome, Italy

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

7. Giuseppina Martella

   1. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
   2. IRCCS Fondazione Santa Lucia, Rome, Italy

   Contribution

   Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8927-7107

8. Paola Imbriani

   1. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
   2. IRCCS Fondazione Santa Lucia, Rome, Italy

   Contribution

   Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3373-5073

9. Paola Bonsi

   IRCCS Fondazione Santa Lucia, Rome, Italy

   Contribution

   Conceptualization, Data curation, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5940-9028

10. Nicola Biagio Mercuri

    1. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
    2. IRCCS Fondazione Santa Lucia, Rome, Italy

    Contribution

    Conceptualization, Supervision, Writing—review and editing

    Competing interests

    No competing interests declared

11. Fabrizio Gardoni

    Department of Pharmacology, University of Milan, Milan, Italy

    Contribution

    Conceptualization, Data curation, Writing—original draft, Writing—review and editing

    Contributed equally with

    Antonio Pisani

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-4598-5563

12. Antonio Pisani

    1. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
    2. IRCCS Fondazione Santa Lucia, Rome, Italy

    Contribution

    Conceptualization, Data curation, Formal analysis, Supervision, Methodology, Writing—original draft, Writing—review and editing

    Contributed equally with

    Fabrizio Gardoni

    For correspondence

    pisani@uniroma2.it

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8432-594X

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