By sculpting the pattern and timing of neuronal electrical activity, inhibitory GABAergic circuits are an ideal candidate for regulating the processes of experience-dependent synaptic modifications. Taking advantage of gene-targeting technology, this hypothesis has been directly tested by abolishing the expression of the 65
kD isoform of GABA-synthetic enzyme, hence reducing activity-dependent GABA synthesis and release at synaptic terminals. Mice that carry such a disruption of the GAD65 gene do not exhibit ocular dominance plasticity in response to monocular deprivation; only an enhancement of inhibition achieved with local delivery of diazepam enables a full rescue of ocular dominance plasticity in these mice [13
Converging results obtained with different experimental approaches have subsequently confirmed the key role of GABAergic inhibition in brain development and plasticity (e.g., [14
]). It is noteworthy that BDNF-overexpressing mice show an accelerated maturation of GABAergic cortical inhibition paralleled by a faster time course of critical period for ocular dominance plasticity [13
], strongly suggesting that the progressive development of the inhibitory tone not only enables the onset of the critical period but subsequently underlies the closure of neural plasticity gates.
One of the major challenges in neuroscience is the development of strategies aimed at promoting nervous system plasticity in adulthood, when recovery from injury and functional rehabilitation are severely hampered. Recently, new evidence has challenged the classic dogma that ocular dominance plasticity is a physiological phenomenon exclusively restricted to the early postnatal development and pointed to a reduction of intracortical inhibition levels as a crucial step for the restoration of plasticity processes in the adult brain. The most direct demonstration that GABAergic inhibition limits plasticity in the adult visual cortex derives from a recent study reporting that pharmacological reduction of intracortical inhibition obtained through the infusion of either MPA (an inhibitor of GABA synthesis) or picrotoxin (a GABAA
antagonist) directly into the visual cortex reactivates ocular dominance plasticity in response to monocular deprivation in adult rats [18
]. Moreover, this treatment leads to a full rescue of long-term potentiation (LTP) of layer II-III field potentials induced by theta-burst stimulation from the white matter, an activity-dependent form of synaptic plasticity which is normally occluded in visual cortical slices from adult animals due to the maturation of inhibitory transmission [18
]. The reduction of intracortical inhibition is accompanied by processes of structural plasticity. The visual cortex of MPA or PTX-treated animals, indeed, shows a decrease in the density of chondroitin sulfate proteoglycans (CSPGs), indicating the activation of endogenous mechanisms of extracellular matrix remodelling which are known to be crucially involved in the expression of neural plasticity [20
]. It is also possible that other molecular components of the extracellular milieu regulating synaptic plasticity in the adult brain, such as myelin proteins [23
] and adhesion molecules [24
], may undergo changes in their expression levels in response to a reduction of intracortical inhibition.
These results show that a brief reduction of GABAergic inhibition is sufficient to reopen a window of plasticity in the visual cortex well after the normal closure of the critical period. Similar conclusions have been drawn from recent evidence showing that the inhibitory tone is a central hub for the restoration of plasticity in the adult visual cortex and that a decrease of intracortical inhibition levels is required for the reinstatement of neural plasticity triggered by different experimental approaches. We demonstrated that environmental enrichment, a condition of increased sensory-motor and cognitive stimulation, reactivates juvenile-like ocular dominance plasticity in the visual cortex of adult rats, with a shift in ocular dominance of cortical neurons following monocular deprivation clearly detectable using both visual evoked potentials and single-unit recordings [25
]. Recovery of plasticity in enriched animals is paralleled by a marked reduction of the inhibitory tone in the visual cortex. Importantly, the decrease of inhibitory neurotransmission is a crucial molecular mechanism underlying the enhancement of visual cortex plasticity induced by environmental enrichment: preventing the reduction of GABAergic inhibition during the period of exposure to environmental enrichment (via micro-osmotic pumps infusing the GABA agonist diazepam into the visual cortex), indeed, completely blocks the ocular dominance shift of cortical neurons in response to monocular deprivation [25
]. The enhanced environmental stimulation provided by environmental enrichment also leads to a twofold enhancement of serotoninergic transmission and to an increase in the number of BDNF-expressing neurons in the visual cortex. Interestingly, infusion of a serotonin synthesis inhibitor not only blocks plasticity in response to monocular deprivation but also fully counteracts the effects produced by environmental enrichment on inhibition and BDNF levels. We suggested a model in which serotonin is the first trigger in the molecular chain set in motion by environmental enrichment, eliciting the decrease of GABA-mediated intracortical inhibition and, in parallel or in series, the enhancement of BDNF levels [25
It is interesting to point out that while, during development, environmental enrichment increases BDNF and accelerates the maturation of inhibition in the visual cortex [15
], in adult animals reared in an enriched environment increased levels of BDNF are associated with reduced GABAergic inhibition. One possible explanation for these apparently contrasting results is that the influence exerted by the environment on these molecular factors may follow a temporarily distinct sequence in the adult compared to the developing brain. Specifically, we propose that the very early (postnatal day 7, see [15
]) increase in BDNF detected in mice reared from birth in an enriched environment may be the prime factor that directly drives the development of inhibitory circuitry in the immature brain; on the contrary, the enhancement of BDNF expression in animals exposed to environmental enrichment in adulthood may occur downstream to the decrease of intracortical inhibition, which could promote the expression of many activity-dependent genes involved in neural plasticity.
Given the central role of serotonin in promoting adult visual cortex plasticity, one might expect that the effects induced by environmental enrichment should be reproducible through an artificial modulation of cerebral levels of this neurotransmitter. This possibility has been addressed in a study by Maya Vetencourt et al. [26
], showing that the administration of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) widely prescribed in the treatment of depression for its capability to enhance extracellular serotonin levels, reinstates plasticity in the visual cortex of adult animals, with treated rats exhibiting a marked shift of ocular dominance in favour of the open eye after one week of monocular deprivation. Also in this case, a pronounced reduction of intracortical inhibition has been detected in the visual cortex, and the osmotic infusion of the GABA agonist diazepam fully prevents the ocular dominance shift induced by monocular deprivation, thus impeding plasticity in fluoxetine-treated animals. Further support to the notion that diffuse projecting systems of the brainstem affect plasticity in adulthood has been very recently provided by the demonstration that a genetic enhancement of nicotinic cholinergic transmission restores ocular dominance plasticity well after the end of the critical period. This effect is abolished by diazepam treatment, suggesting that the cholinergic signalling mechanisms may adjust excitatory-inhibitory balance [27
Using an approach quite different from environmental enrichment, a study by He and colleagues reported that exposing adult animals to complete darkness can also promote plasticity in the visual cortex [28
]. These authors provided indirect evidence that the enhanced cortical plasticity might be related to a shift in the balance between inhibition and excitation towards levels more similar to those found in the immature cortex, caused by a reduced expression of GABAA
receptors relative to AMPA receptors. This suggestion has been confirmed in a very recent study [29
] showing that dark exposure decreases inhibitory synaptic density and paired-pulse depression and reinstates in the visual cortex the expression of endocannabinoid-dependent inhibitory long-term depression, a form of synaptic plasticity normally restricted to the juvenile age [30
Two different hypotheses, not mutually exclusive, could be formulated for explaining how the reduction of the inhibitory tone to juvenile-like levels leads to a recovery of cerebral plasticity in the adult brain. According to one hypothesis, the maturation of GABAergic intracortical transmission sets the point after which the editing activity of visual cortex pyramidal neurons enables ocular dominance plasticity; as development proceeds further, the inhibitory tone surpasses a threshold, and this causes the closure of the critical period. A reduction of inhibition levels may reinstate in the adult visual cortex the capability of binocular neurons to detect the imbalance in retinal inputs induced by the closure of one eye. According to an alternative hypothesis, the overall increase of cortical activity due to the shift in excitation-inhibition balance is the key factor favoring plasticity recovery. Activity-dependent regulation of gene expression could induce a genetic transcriptional program critical for promoting plasticity.