Tommaso Pizzorusso

BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex

Maturation of the visual cortex is influenced by visual experience during an early postnatal period. The factors that regulate such a critical period remain unclear. We examined the maturation and plasticity of the visual cortex in transgenic mice in which the postnatal rise of brain-derived neurotrophic factor (BDNF) was accelerated. In these mice, the maturation of GABAergic innervation and inhibition was accelerated. Furthermore, the age-dependent decline of cortical long-term potentiation induced by white matter stimulation, a form of synaptic plasticity sensitive to cortical inhibition, occurred earlier. Finally, transgenic mice showed a precocious development of visual acuity and an earlier termination of the critical period for ocular dominance plasticity. We propose that BDNF promotes the maturation of cortical inhibition during early postnatal life, thereby regulating the critical period for visual cortical plasticity.

Functional postnatal development of the rat primary visual cortex and the role of visual experience: Dark rearing and monocular deprivation

Postnatal development of rat visual cortical functions was studied by recording extracellularly from the primary visual cortex of 22 animals ranging in age from postnatal day 17 (P17) to P45. We found that in the youngest animals (P17-P19) all visual cortical functions tested were immature. Selectivity for orientation and movement direction of visual stimuli was almost absent, most cells received binocular input and their mean receptive field size was 5-6 times the adult size. Visual acuity was half its adult value. These functional properties developed gradually during the following weeks and by P45 they were all adult-like. This functional development is affected by manipulations of the visual input such as dark rearing (DR) and monocular deprivation (MD). DR prevented the normal postnatal maturation of visual cortical functions: in P60 rats, dark reared from birth, their visual cortical functions resembled those of P19-P21 rats. MD from P15 to P45 resulted in a dramatic shift of the ocular dominance distribution (ODD) in favour of the open eye and in a loss of visual acuity for the deprived eye. To determine the sensitive period of rat visual cortex to MD (critical period) we evaluated the shift in ODD of visual cortical neurones in rats that were subjected to the progressive delay of the onset of fixed MD period (10 days). Our results show that the critical period begins around the end of the third postnatal week, peaks between the fourth and fifth week and starts to decline from the end of the fifth week.

A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression.

Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments.

Critical periods during sensory development

Recent studies have made progress in characterizing the determinants of critical periods for experience-dependent plasticity. They highlight the role of neurotrophins, NMDA receptors and GABAergic inhibition. In particular, genetic manipulation of a single molecule, brain-derived neurotrophic factor (BDNF), has been shown to alter the timing of the critical period of plasticity in mouse visual cortex, establishing a causal relation between neurotrophin action, the development of visual function, and the duration of the critical period.

Molecular basis of plasticity in the visual cortex.

Sensory experience is known to shape the maturation of cortical circuits during development. A paradigmatic example is the effect of monocular deprivation on ocular dominance of visual cortical neurons. Although visual cortical plasticity has been widely studied since its initial discovery by Hubel and Wiesel >40 years ago, the description of the underlying molecular mechanisms has lagged behind. Several new findings are now beginning to close this gap. Recent data deepen our knowledge of the factors involved in the intercellular communication and intracellular signaling that mediate experience-dependent plasticity in the developing visual cortex. In addition, new findings suggest a role for the extracellular matrix in inhibition of ocular-dominance plasticity in the adult visual cortex.

Animals lacking link protein have attenuated perineuronal nets and persistent plasticity.

Chondroitin sulphate proteoglycans in the extracellular matrix restrict plasticity in the adult central nervous system and their digestion with chondroitinase reactivates plasticity. However the structures in the extracellular matrix that restrict plasticity are unknown. There are many changes in the extracellular matrix as critical periods for plasticity close, including changes in chondroitin sulphate proteoglycan core protein levels, changes in glycosaminoglycan sulphation and the appearance of dense chondroitin sulphate proteoglycan-containing perineuronal nets around many neurons. We show that formation of perineuronal nets is triggered by neuronal production of cartilage link protein Crtl1 (Hapln1), which is up-regulated in the visual cortex as perineuronal nets form during development and after dark rearing. Mice lacking Crtl1 have attenuated perineuronal nets, but the overall levels of chondroitin sulphate proteoglycans and their pattern of glycan sulphation are unchanged. Crtl1 knockout animals retain juvenile levels of ocular dominance plasticity and their visual acuity remains sensitive to visual deprivation. In the sensory pathway, axons in knockout animals but not controls sprout into the party denervated cuneate nucleus. The organization of chondroitin sulphate proteoglycan into perineuronal nets is therefore the key event in the control of central nervous system plasticity by the extracellular matrix.

Requirement of the nicotinic acetylcholine receptor β2 subunit for the anatomical and functional development of the visual system

In the mammalian visual system the formation of eye-specific layers at the thalamic level depends on retinal waves of spontaneous activity, which rely on nicotinic acetylcholine receptor activation. We found that in mutant mice lacking the β2 subunit of the neuronal nicotinic receptor, but not in mice lacking the α4 subunit, retinofugal projections do not segregate into eye-specific areas, both in the dorso-lateral geniculate nucleus and in the superior colliculus. Moreover, β2−/− mice show an expansion of the binocular subfield of the primary visual cortex and a decrease in visual acuity at the cortical level but not in the retina. We conclude that the β2 subunit of the nicotinic acetylcholine receptor is necessary for the anatomical and functional development of the visual system.

Brain-derived neurotrophic factor and nerve growth factor potentiate excitatory synaptic transmission in the rat visual cortex.

1. The effect of brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) on excitatory synaptic transmission in the developing visual cortex was studied by whole‐cell patch‐clamp recordings from rat brain slices. 2. Both neurotrophins induced a rapid increase in the amplitude of impulse‐evoked excitatory postsynaptic currents (EPSCs). BDNF also increased the frequency of spontaneous EPSCs. 3. Analysis of the currents revealed that alpha‐amino‐3‐hydroxy‐5‐methyl‐isoxazole propionic acid (AMPA) and N‐methyl‐D‐aspartate (NMDA) receptor‐mediated components contributing to the EPSC peak amplitude were equally potentiated by the neurotrophins. 4. When synaptic transmission was studied by minimal stimulation of intracortical afferents, neurotrophins induced a decrease in the occurrence of release failures. 5. A number of neurones were insensitive to the effects of the neurotrophins, possibly related to the considerable heterogeneity of neuronal types and to the uneven distribution of neurotrophin receptors in the visual cortex. 6. The probability of neurotransmitter release represents a rapidly modifiable synaptic feature by which neurotrophins can potentiate the efficacy of excitatory synaptic transmission in the visual cortex.

Reducing Intracortical Inhibition in the Adult Visual Cortex Promotes Ocular Dominance Plasticity

Experience-dependent plasticity in the cortex is often higher during short critical periods in postnatal development. The mechanisms limiting adult cortical plasticity are still unclear. Maturation of intracortical GABAergic inhibition is suggested to be crucial for the closure of the critical period for ocular dominance (OD) plasticity in the visual cortex. We find that reduction of GABAergic transmission in the adult rat visual cortex partially reactivates OD plasticity in response to monocular deprivation (MD). This is accompanied by an enhancement of activity-dependent potentiation of synaptic efficacy but not of activity-dependent depression. We also found a decrease in the expression of chondroitin sulfate proteoglycans in the visual cortex of MD animals with reduced inhibition, after the reactivation of OD plasticity. Thus, intracortical inhibition is a crucial limiting factor for the induction of experience-dependent plasticity in the adult visual cortex.

Developmental Downregulation of Histone Posttranslational Modifications Regulates Visual Cortical Plasticity

The action of visual experience on visual cortical circuits is maximal during a critical period of postnatal development. The long-term effects of this experience are likely mediated by signaling cascades regulating experience-dependent gene transcription. Developmental modifications of these pathways could explain the difference in plasticity between the young and adult cortex. We studied the pathways linking experience-dependent activation of ERK to CREB-mediated gene expression in vivo. In juvenile mice, visual stimulation that activates CREB-mediated gene transcription also induced ERK-dependent MSK and histone H3 phosphorylation and H3-H4 acetylation, an epigenetic mechanism of gene transcription activation. In adult animals, ERK and MSK were still inducible; however, visual stimulation induced weak CREB-mediated gene expression and H3-H4 posttranslational modifications. Stimulation of histone acetylation in adult animals by means of trichostatin promoted ocular dominance plasticity. Thus, differing, experience-dependent activations of signaling molecules might be at the basis of the differences in experience-dependent plasticity between juvenile and adult cortex.