**3. ECM-guided switch from juvenile to adult synaptic plasticity**

Early in life, high structural plasticity allows profound shaping of brain circuits by experience. Such critical periods in the juvenile brain are limited by the occurrence of the ECM imple‐ menting adult brain plasticity modes. For instance, in wild-type animals, dark rearing delays not only the critical periods of developmental plasticity in visual cortex of rodents, but also the formation of PNNs. During the development, the cartilage link protein Crtl1/Hapln1 is organizing the formation of PNNs. Crtl1/Hapln1 k.o. mice do not develop normal PNN structures in the visual cortex. These mice show juvenile forms of ocular dominance (OD) plasticity and sensitivity of the visual system to deprivation throughout the life-span [9].

The seminal study by Pizzorusso et al. [10] has elucidated the ECM as the regulatory switch between juvenile and adult plasticity. The authors combined monocular deprivation with injection of the ECM-cleaving enzyme chondroitinase ABC (chABC) into visual cortex of adult rats (see also **Figure 1C**). The local weakening of the ECM "re-juvenated" the visual cortex and restored the critical period form of OD plasticity (**Figure 2**). By the same manipulation Pizzorusso and colleagues restored in a follow-up study, the visual acuity in adult animals grown up with long-term monocular deprivation [11]. Similarly, application of the serine protease tissue-type plasminogen activator (tPA) into the visual cortex can prolong or reactivate critical periods of OD plasticity in visual cortex [12] based on increased structural remodeling [13].

Later studies identified the regulatory role of the ECM in other forms of developmental plasticity during brain maturation of different vertebrate species. For instance, birdsong learning in the zebra finch occurs during a sensitive period similar to the language develop‐ ment in humans. It has been shown that with the end of this critical period PNNs around PVpositive neurons emerge in brain areas that are dedicated to singing [14]. In another set of experiments, Gogolla et al. [15] shown that the maturing ECM in the amygdala essentially makes fear memories erasure resistant in adult animals. In rats not older than 3–4 weeks, a conditioned fear memory trace can be erased permanently by extinction, that is, the presen‐ tation of the conditioned stimulus without the aversive stimulus. However, after this period extinction only attenuates the fear response, but it reinstates instantaneously if the aversive stimulus is presented again. Hence, a permanent loss of the fear memory is only found before the ECM in the amygdala is formed and is preserving established fear memories. Gogolla and colleagues now attenuated the ECM in the amygdala by chABC injections in adult rats. This led to a complete erasure of the fear response after an extinction phase even if the aversive stimulus is presented to these animals again. In addition, the early preweaning environment impacts on rodent ECM maturation in a functional manner. Improved performance in water maze learning in the adult age after early postnatal-enriched housing has been correlated with increased PNN formation in the striatum reflecting functional shaping of neuronal circuits involved in motor learning [16].

Neuronal Plasticity in the Juvenile and Adult Brain Regulated by the Extracellular Matrix http://dx.doi.org/10.5772/62452 147

several ECM-based mechanisms for regulating synaptic plasticity and its effects on brain

Early in life, high structural plasticity allows profound shaping of brain circuits by experience. Such critical periods in the juvenile brain are limited by the occurrence of the ECM imple‐ menting adult brain plasticity modes. For instance, in wild-type animals, dark rearing delays not only the critical periods of developmental plasticity in visual cortex of rodents, but also the formation of PNNs. During the development, the cartilage link protein Crtl1/Hapln1 is organizing the formation of PNNs. Crtl1/Hapln1 k.o. mice do not develop normal PNN structures in the visual cortex. These mice show juvenile forms of ocular dominance (OD) plasticity and sensitivity of the visual system to deprivation throughout the life-span [9].

The seminal study by Pizzorusso et al. [10] has elucidated the ECM as the regulatory switch between juvenile and adult plasticity. The authors combined monocular deprivation with injection of the ECM-cleaving enzyme chondroitinase ABC (chABC) into visual cortex of adult rats (see also **Figure 1C**). The local weakening of the ECM "re-juvenated" the visual cortex and restored the critical period form of OD plasticity (**Figure 2**). By the same manipulation Pizzorusso and colleagues restored in a follow-up study, the visual acuity in adult animals grown up with long-term monocular deprivation [11]. Similarly, application of the serine protease tissue-type plasminogen activator (tPA) into the visual cortex can prolong or reactivate critical periods of OD plasticity in visual cortex [12] based on increased structural

Later studies identified the regulatory role of the ECM in other forms of developmental plasticity during brain maturation of different vertebrate species. For instance, birdsong learning in the zebra finch occurs during a sensitive period similar to the language develop‐ ment in humans. It has been shown that with the end of this critical period PNNs around PVpositive neurons emerge in brain areas that are dedicated to singing [14]. In another set of experiments, Gogolla et al. [15] shown that the maturing ECM in the amygdala essentially makes fear memories erasure resistant in adult animals. In rats not older than 3–4 weeks, a conditioned fear memory trace can be erased permanently by extinction, that is, the presen‐ tation of the conditioned stimulus without the aversive stimulus. However, after this period extinction only attenuates the fear response, but it reinstates instantaneously if the aversive stimulus is presented again. Hence, a permanent loss of the fear memory is only found before the ECM in the amygdala is formed and is preserving established fear memories. Gogolla and colleagues now attenuated the ECM in the amygdala by chABC injections in adult rats. This led to a complete erasure of the fear response after an extinction phase even if the aversive stimulus is presented to these animals again. In addition, the early preweaning environment impacts on rodent ECM maturation in a functional manner. Improved performance in water maze learning in the adult age after early postnatal-enriched housing has been correlated with increased PNN formation in the striatum reflecting functional shaping of neuronal circuits

**3. ECM-guided switch from juvenile to adult synaptic plasticity**

development and adult learning behavior.

146 Composition and Function of the Extracellular Matrix in the Human Body

remodeling [13].

involved in motor learning [16].

**Figure 2. The emerging ECM during brain maturation and its regulatory role for juvenile brain plasticity** (**A**) *Wiste‐ ria floribunda* (WFA) fluorescein staining against sugar chains of the CSPGs in rodent sensory cortex shows that the diffuse HA-based ECM and perineuronal nets around cells emerge with brain maturation (≥3 month), but were abun‐ dant in juvenile state (3 weeks). Modified from Ref. [42]. (**B**) Pizzorusso et al. [10] demonstrated the inhibitory role of the developmental maturation of the ECM in visual cortex of rats for early experience-dependent plasticity. In juvenile rats, monocular deprivation (MD) leads to an ocular dominance shift (left). After the critical period, MD alone did not cause such a shift in the adult. In this study, the authors found that weakening of the ECM by chABC treatment in visual cortex reactivated OD plasticity shifting toward the nondeprived eye.

The emerging ECM in the developing brain seems to be involved in a complex molecular machinery organizing the maturation of neuronal networks. For instance, in mouse visual cortex, it has been shown that critical periods are initiated, maintained, and closed by the action of the orthodenticle homeobox 2 homeoprotein (Otx2) on PV+-GABAergic interneurons [17]. Interestingly, Otx2 contains a glycosaminoglycan binding sequence that mediates its allocation to the PNNs by specific binding to CS D and E. Thereby, a constant level of Otx2 in PV+-neurons keeps a mature, consolidated, and persistent PNN-state in the adult brain. Hydrolysis of the PNNs by chABC reduces the amount of endogenous Otx2 in PV cells mediating the reopening of OD plasticity in adult mice [18].

The reviewed studies in this paragraph have shown how the change of the juvenile form of the ECM to a more rigid adult ECM mediates the different modes of neuronal plasticity during brain development. Why has this restriction of adult reorganizational and regenerative plasticity only evolved in higher vertebrates? The evolutionary benefit may be to preserve the costly acquired hardwired connections during early life experience, which are fundamental for rapid experience-based behavioral adaptations of higher vertebrates [4]. Nonetheless, the adult, healthy brain retains a remarkable capability of plastic reorganization that is essential for constantly adapting to our ever-changing environment.
