Hirofumi Morishita

Lynx1, a Cholinergic Brake, Limits Plasticity in Adult Visual Cortex

Lynx Vision Early in development, correct visual experiences during the so-called “critical period” build the foundations for visual function in adulthood. Hence, when one eye is not working together with the other, an adult may be left with imperfect vision. The plasticity characteristic of the critical period does not persist into adulthood, and later readjustments to visual function may not be fully successful. Morishita et al. (p. 1238, published online 11 November; see the Perspective by Higley and Strittmatter) have identified a gene in mice called Lynx1, which shows increased expression after the critical period. The Lynx1 protein binds to and reduces the sensitivity of acetylcholine receptors, but if mice were treated to enhanced cholinergic signaling, their adult visual plasticity was improved and if mice lacked the Lynx1 gene altogether, they were able to recover visual function even in adulthood. A gene identified in the mouse may show the way to improved treatments for amblyopia, a condition of indistinct vision. Experience-dependent brain plasticity typically declines after an early critical period during which circuits are established. Loss of plasticity with closure of the critical period limits improvement of function in adulthood, but the mechanisms that change the brain’s plasticity remain poorly understood. Here, we identified an increase in expression of Lynx1 protein in mice that prevented plasticity in the primary visual cortex late in life. Removal of this molecular brake enhanced nicotinic acetylcholine receptor signaling. Lynx1 expression thus maintains stability of mature cortical networks in the presence of cholinergic innervation. The results suggest that modulating the balance between excitatory and inhibitory circuits reactivates visual plasticity and may present a therapeutic target.

Perineuronal nets protect fast-spiking interneurons against oxidative stress

A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.

Prefrontal Cortex and Social Cognition in Mouse and Man

Social cognition is a complex process that requires the integration of a wide variety of behaviors, including salience, reward-seeking, motivation, knowledge of self and others, and flexibly adjusting behavior in social groups. Not surprisingly, social cognition represents a sensitive domain commonly disrupted in the pathology of a variety of psychiatric disorders including Autism Spectrum Disorder (ASD) and Schizophrenia (SCZ). Here, we discuss convergent research from animal models to human disease that implicates the prefrontal cortex (PFC) as a key regulator in social cognition, suggesting that disruptions in prefrontal microcircuitry play an essential role in the pathophysiology of psychiatric disorders with shared social deficits. We take a translational perspective of social cognition, and review three key behaviors that are essential to normal social processing in rodents and humans, including social motivation, social recognition, and dominance hierarchy. A shared prefrontal circuitry may underlie these behaviors. Social cognition deficits in animal models of neurodevelopmental disorders like ASD and SCZ have been linked to an altered balance of excitation and inhibition (E/I ratio) within the cortex generally, and PFC specifically. A clear picture of the mechanisms by which altered E/I ratio in the PFC might lead to disruptions of social cognition across a variety of behaviors is not well understood. Future studies should explore how disrupted developmental trajectory of prefrontal microcircuitry could lead to altered E/I balance and subsequent deficits in the social domain.

Structure of the cadherin-related neuronal receptor/ protocadherin-α first extracellular cadherin domain reveals diversity across cadherin families

The recent explosion in genome sequencing has revealed the great diversity of the cadherin superfamily. Within the superfamily, protocadherins, which are expressed mainly in the nervous system, constitute the largest subgroup. Nevertheless, the structures of only the classical cadherins are known. Thus, to broaden our understanding of the adhesion repertoire of the cadherin superfamily, we determined the structure of the N-terminal first extracellular cadherin domain of the cadherin-related neuronal receptor/protocadherin-α4. The hydrophobic pocket essential for homophilic adhesiveness in the classical cadherins was not found, and the functional significance of this structural domain was supported by exchanging the first extracellular cadherin domains of protocadherin and classical cadherin. Moreover, potentially crucial variations were observed mainly in the loop regions. These included the protocadherin-specific disulfide-bonded Cys-X5-Cys motif, which showed Ca2+-induced chemical shifts, and the RGD motif, which has been suggested to be involved in heterophilic cell adhesion via the active form of β1 integrin. Our findings reveal that the adhesion repertoire of the cadherin superfamily is far more divergent than would be predicted by studying the classical cadherins alone.

Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons

BACKGROUND Oxidative stress and the specific impairment of perisomatic gamma-aminobutyric acid circuits are hallmarks of the schizophrenic brain and its animal models. Proper maturation of these fast-spiking inhibitory interneurons normally defines critical periods of experience-dependent cortical plasticity. METHODS Here, we linked these processes by genetically inducing a redox dysregulation restricted to such parvalbumin-positive cells and examined the impact on critical period plasticity using the visual system as a model (3-6 mice/group). RESULTS Oxidative stress was accompanied by a significant loss of perineuronal nets, which normally enwrap mature fast-spiking cells to limit adult plasticity. Accordingly, the neocortex remained plastic even beyond the peak of its natural critical period. These effects were not seen when redox dysregulation was targeted in excitatory principal cells. CONCLUSIONS A cell-specific regulation of redox state thus balances plasticity and stability of cortical networks. Mistimed developmental trajectories of brain plasticity may underlie, in part, the pathophysiology of mental illness. Such prolonged developmental plasticity may, in turn, offer a therapeutic opportunity for cognitive interventions targeting brain plasticity in schizophrenia.

CNR/Pcdhα family in subplate neurons, and developing cortical connectivity

The cadherin-related neuronal receptor (CNR)/protocadherin (Pcdh) &agr; family is one of the diverse protocadherin families identified as a candidate diversified membrane-associated component regulating the formation of neuronal connectivity. However, its expression during neural circuit formation has not been examined in detail. Here, we used a conserved sequence to study the expression of this protein family during the development of neocortical connectivity, by immunohistochemistry and in situ hybridization. The proteins were detected in developing thalamocortical and corticofugal axons, and in subplate neurons, which pioneer these axon tracts. The expression in subplate neurons was confirmed by birth-date labeling with BrdU, and by examination in homozygous reeler mice. This pattern of CNR/Pcdh&agr; expression suggests its involvement in the development of neocortical connectivity.

Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia

Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.

Regulating critical period plasticity: insight from the visual system to fear circuitry for therapeutic interventions.

Early temporary windows of heightened brain plasticity called critical periods developmentally sculpt neural circuits and contribute to adult behavior. Regulatory mechanisms of visual cortex development – the preeminent model of experience-dependent critical period plasticity-actively limit adult plasticity and have proved fruitful therapeutic targets to reopen plasticity and rewire faulty visual system connections later in life. Interestingly, these molecular mechanisms have been implicated in the regulation of plasticity in other functions beyond vision. Applying mechanistic understandings of critical period plasticity in the visual cortex to fear circuitry may provide a conceptual framework for developing novel therapeutic tools to mitigate aberrant fear responses in post traumatic stress disorder. In this review, we turn to the model of experience-dependent visual plasticity to provide novel insights for the mechanisms regulating plasticity in the fear system. Fear circuitry, particularly fear memory erasure, also undergoes age-related changes in experience-dependent plasticity. We consider the contributions of molecular brakes that halt visual critical period plasticity to circuitry underlying fear memory erasure. A major molecular brake in the visual cortex, perineuronal net formation, recently has been identified in the development of fear systems that are resilient to fear memory erasure. The roles of other molecular brakes, myelin-related Nogo receptor signaling and Lynx family proteins – endogenous inhibitors for nicotinic acetylcholine receptor, are explored in the context of fear memory plasticity. Such fear plasticity regulators, including epigenetic effects, provide promising targets for therapeutic interventions.

Myelination triggers local loss of axonal CNR/protocadherinα family protein expression

The cadherin‐related neuronal receptor (CNR)/protocadherin (Pcdh) α family is one of the diverse protocadherin families expressed in developing axons. We observed a strong axonal expression of these proteins at late embryonic and early postnatal stages corresponding to regions where fibers had not yet been myelinated. We therefore followed the postnatal localization of CNR/Pcdhα protein in major axonal tracts, such as the internal capsule, lateral olfactory tract, and optic nerve, and found that its axonal localization was dramatically lost in parallel with the increased expression of myelin markers. Moreover, the hypomyelinated optic nerve tracts of the myelin‐deficient Shiverer mouse exhibited elevated levels of CNR/Pcdhα expression. These axonal expression patterns of CNR/Pcdhα in wild‐type and Shiverer mice were similar to those of growth associated protein 43 (GAP‐43) and L1, both of which are associated with axonal maturation. Thus, myelination may be a trigger for the local loss of axonal CNR/Pcdhα protein, and this process may be important in the maturation of neural circuits.

Stability, occurrence and step morphology of polymorphs and polytypes of stearic acid: I. Stability and occurrence

Abstract The thermodynamical stability and occurrence of three different structural modifications: monoclinic and pseudo-orthorhombic polytypes of the B polymorph, called B(mon) and B(orth II) respectively, and monoclinic C polymorph, C(mon), of stearic acid have been examined. The solubility measurements, overgrowth and isothermal crystallization proved that B(orth II) and C(mon) are most stable below and above 32°C, respectively, whereas B(mon) is always metastable, turning to be more stable than C(mon) below between 23 and 24°C. It was confirmed by micro-probe Raman spectroscopy that the polytypic structure of the newly-overgrown crystal on the (001) faces of the seed crystal of B(mon) changed from the original monoclinic to pseudo-orthorhombic, B(orth II), at very small supersaturations above 23°C. This conversion was caused by the solubility difference. The occurrence experiment indicated a slight tendency that B(mon) crystallized more than B(orth II) at lower temperatures.