GABAergic inhibition in visual cortical plasticity

Abstract

Experience is required for the shaping and refinement of developing neural circuits during well defined periods of early postnatal development called critical periods. Many studies in the visual cortex have shown that intracortical GABAergic circuitry plays a crucial role in defining the time course of the critical period for ocular dominance plasticity. With the end of the critical period, neural plasticity wanes and recovery from the effects of visual defects on visual acuity (amblyopia) or binocularity is much reduced or absent. Recent results pointed out that intracortical inhibition is a fundamental limiting factor for adult cortical plasticity and that its reduction by means of different pharmacological and environmental strategies makes it possible to greatly enhance plasticity in the adult visual cortex, promoting ocular dominance plasticity and recovery from amblyopia. Here we focus on the role of intracortical GABAergic circuitry in controlling both developmental and adult cortical plasticity. We shall also discuss the potential clinical application of these findings to neurological disorders in which synaptic plasticity is compromised because of excessive intracortical inhibition.

Keywords: GABA; amblyopia; critical period; environmental enrichment; ocular dominance plasticity.

Figure 1

Time course of the critical period (CP) for ocular dominance (OD) plasticity in response to monocular deprivation in rodents; OD plasticity is normalized to the CP peak's level. CP onset can be anticipated by increasing intracortical inhibition through benzodiazepine treatment or PSA (see text) removal (green arrow pointing left). Conversely, the end of the CP can be delayed by preventing the maturation of GABAergic inhibition through dark rearing from birth (red arrow pointing right). The effects of dark rearing can be counteracted by concomitant EE (see text). BDNF over-expression promotes a faster maturation of GABAergic interneurons, acting both on the onset and on the closure of the CP, thus shifting leftward the entire developmental plasticity curve.

Figure 2

Developmental increase of brain GABAergic inhibition levels (normalized to the normal adult values; red curve) is paralleled by a progressive reduction of experience-dependent plasticity. Plasticity is high during early development (green block) and very low in the adult brain (yellow block). Anomalous increases in the strength of inhibitory neural circuits may lead to over-inhibition linked to permanent deficits in synaptic plasticity and neural development, like in the Rett syndrome and in the Down's syndrome. Reducing GABAergic inhibition with pharmacological (blockers of GABA synthesis or GABA receptor antagonists, fluoxetine) or environmental (EE, and dark exposure) treatments can increase plasticity in the adult brain, enabling OD plasticity and favoring recovery from amblyopia. The capability of EE to reduce GABAergic inhibition makes this paradigm eligible for therapeutic applications also in the treatment of developmental intellectual disabilities.