Nicotinic regulation of experience-dependent plasticity in visual cortex.

While the cholinergic neuromodulatory system and muscarinic acetylcholine receptors (AChRs) have been appreciated as permissive factors for developmental critical period plasticity in visual cortex, it was unknown why plasticity becomes limited after the critical period even in the presence of massive cholinergic projections to visual cortex. In this review we highlighted the recent progresses that started to shed light on the role of the nicotinic cholinergic neuromodulatory signaling on limiting juvenile form of plasticity in the adult brain. We introduce the Lynx family of proteins and Lynx1 as its representative, as endogenous proteins structurally similar to α-bungarotoxin with the ability to bind and modulate nAChRs to effectively regulate functional and structural plasticity. Remarkably, Lynx family members are expressed in distinct subpopulations of GABAergic interneurons, placing them in unique positions to potentially regulate the convergence of GABAergic and nicotinic neuromodulatory systems to regulate plasticity. Continuing studies of the potentially differential roles of Lynx family of proteins may further our understanding of the fundamentals of molecular and cell type-specific mechanisms of plasticity that we may be able to harness through nicotinic cholinergic signaling.

Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex.

UNLABELLED: Dendritic spine turnover becomes limited in the adult cerebral cortex. Identification of specific aspects of spine dynamics that can be unmasked in adulthood and its regulatory molecular mechanisms could provide novel therapeutic targets for inducing plasticity at both the functional and structural levels for robust recovery from brain disorders and injuries in adults. Lynx1, an endogenous inhibitor of nicotinic acetylcholine receptors, was previously shown to increase its expression in adulthood and thus to limit functional ocular dominance plasticity in adult primary visual cortex (V1). However, the role of this "brake" on spine dynamics is not known. We examined the contribution of Lynx1 on dendritic spine turnover before and after monocular deprivation (MD) in adult V1 with chronic in vivo imaging using two-photon microscopy and determined the spine turnover rate of apical dendrites of layer 5 (L5) and L2/3 pyramidal neurons in adult V1 of Lynx1 knock-out (KO) mice. We found that the deletion of Lynx1 doubled the baseline spine turnover rate, suggesting that the spine dynamics in the adult cortex is actively limited by the presence of Lynx1. After MD, adult Lynx1-KO mice selectively exhibit higher rate of spine loss with no difference in gain rate in L5 neurons compared with control wild-type counterparts, revealing a key signature of spine dynamics associated with robust functional plasticity in adult V1. Overall, Lynx1 could be a promising therapeutic target to induce not only functional, but also structural plasticity at the level of spine dynamics in the adult brain. SIGNIFICANCE STATEMENT: Dendritic spine turnover becomes limited in the adult cortex. In mouse visual cortex, a premier model of experience-dependent plasticity, we found that the deletion of Lynx1, a nicotinic "brake" for functional plasticity, doubled the baseline spine turnover in adulthood, suggesting that the spine dynamics in the adult cortex is actively limited by Lynx1. After visual deprivation, spine loss, but not gain rate, remains higher in adult Lynx1 knock-out mice than in control wild-type mice, revealing a key signature of spine dynamics associated with robust functional plasticity. Lynx1 would be a promising target to induce not only functional, but also structural plasticity at the level of spine dynamics in adulthood.

Neuraminidase-Dependent Degradation of Polysialic Acid Is Required for the Lamination of Newly Generated Neurons.

Hippocampal granule cells (GCs) are generated throughout the lifetime and are properly incorporated into the innermost region of the granule cell layer (GCL). Hypotheses for the well-regulated lamination of newly generated GCs suggest that polysialic acid (PSA) is present on the GC surface to modulate GC-to-GC interactions, regulating the process of GC migration; however, direct evidence of this involvement is lacking. We show that PSA facilitates the migration of newly generated GCs and that the activity of N-acetyl-α-neuraminidase 1 (NEU1, sialidase 1) cleaves PSA from immature GCs, terminating their migration in the innermost GCL. Developing a migration assay of immature GCs in vitro, we found that the pharmacological depletion of PSA prevents the migration of GCs, whereas the inhibition of PSA degradation with a neuraminidase inhibitor accelerates this migration. We found that NEU1 is highly expressed in immature GCs. The knockdown of NEU1 in newly generated GCs in vivo increased PSA presence on these cells, and attenuated the proper termination of GC migration in the innermost GCL. In conclusion, this study identifies a novel mechanism that underlies the proper lamination of newly generated GCs through the modulation of PSA presence by neuronal NEU1.

[Critical period mechanisms: implication for neurodevelopmental and psychiatric disorders].

Our behavior reflects the neural circuits sculpted by our experiences during early temporary windows of heightened brain plasticity called critical periods. Such heightened plasticity declines in adulthood, often limiting recovery of function. On the other hand, the adult brain also needs stability. Failed stabilization can disrupt circuit computations by allowing modification by undesirable information, which may lead to mental disorders. Understanding the mechanisms regulating the critical periods of neural plasticity can provide insights toward therapeutic interventions for neurodevelopmental and psychiatric disorders. In this review, we discuss the potential contributions of "molecular brakes" on the critical period plasticity in the visual system to the etiology of psychiatric disorders. Interestingly, recent findings for the pathophysiological changes associated with schizophrenia indicate excessive plasticity due to the removal of molecular brakes. Applying the mechanistic understandings of critical period plasticity in the visual system to cognitive development may provide a conceptual framework for exploring novel endophenotypes and therapeutic approaches to treat psychiatric disorders.

Dose response effects of 810 nm laser light on mouse primary cortical neurons.

BACKGROUND AND OBJECTIVES: In the past four decades numerous studies have reported the efficacy of low level light (laser) therapy (LLLT) as a treatment for diverse diseases and injuries. Recent studies have shown that LLLT can biomodulate processes in the central nervous system and has been extensively studied as a stroke treatment. However there is still a lack of knowledge on the effects of LLLT at the cellular level in neurons. The present study aimed to study the effect of 810 nm laser on several cellular processes in primary cortical neurons cultured from embryonic mouse brains. STUDY DESIGN/MATERIALS AND METHODS: Neurons were irradiated with fluences of 0.03, 0.3, 3, 10, or 30 J/cm(2) of 810-nm laser delivered over varying times at 25 mW/cm(2) and intracellular levels of reactive oxygen species (ROS), nitric oxide and calcium were measured using fluorescent probes within 5 minutes of the end of irradiation. The changes in mitochondrial function in response to light were studied in terms of adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP). RESULTS: Light induced a significant increase in calcium, ATP and MMP at lower fluences and a decrease at higher fluences. ROS was significantly induced at low fluences, followed by a decrease and a second larger increase at 30 J/cm(2). Nitric oxide levels showed a similar pattern of a double peak but values were less significant compared to ROS. CONCLUSIONS: The results suggest that LLLT at lower fluences is capable of inducing mediators of cell signaling processes which in turn may be responsible for the beneficial stimulatory effects of the low level laser. At higher fluences beneficial mediators are reduced and high levels of Janus-type mediators such as ROS and NO (beneficial at low concentrations and harmful at high concentrations) may be responsible for the damaging effects of high-fluence light and the overall biphasic dose response.

Prenatal stress inhibits neuronal maturation through downregulation of mineralocorticoid receptors.

Prenatal stress (PS) increases the risk of depressive disorders in adult offspring. The pathophysiology of depressive disorders has been linked to hippocampal dysfunction; however, whether and how PS attenuates the development and function of hippocampal networks remains unknown. Using a rat model of PS, in which pregnant mothers receive daily restraint stress during late gestation and their offspring exhibit depressive-like behavior later in life, we show that PS impairs the morphological and functional maturation of hippocampal granule cells in adult offspring via the downregulated expression of mineralocorticoid receptors. PS reduced the dendritic complexity and spine density of neonatal-generated granule cells, which persists into adulthood. These granule cells exhibited depressed synaptic responses to stimulation of the medial perforant path. We further revealed that the expression of mineralocorticoid receptors, which we found is necessary for proper dendritic maturation in this study, was significantly downregulated in granule cells after PS. These results suggest that PS-induced downregulation of mineralocorticoid receptors attenuates neuronal maturation, which results in dysfunction of neuronal network in adulthood.