Real-time neuronal homeostasis by coordinating VGSC intrinsic properties

Homeostasis of internal environment and cellular metabolism ensures cells’ functions to be stable in living organisms. Cellular homeostasis is believed to be maintained via feedback or feedforward manners. We report a novel mechanism that maintains neuronal homeostasis through coordinating the intrinsic properties of single molecules concurrently. Spike encoding and sodium channel dynamics at cortical neurons were studied by patch-clamp recording. Voltage-gated sodium channels set refractory period and threshold potential toward different directions to stabilize the energetic barrier for firing sequential action potentials. This neuronal homeostasis is not affected by intracellular Ca²⁺ signals and membrane potentials. Real-time homeostasis maintains precise and reliable neuronal encoding without any destabilization.     

Plasticity of neuronal receptors

This article describes ways in which receptors, key components of signal propagation through a synapse, can mediate changes in that propagation. Changes occur at four levels: in the signal-transducing capability of a single receptor molecule, in the number of receptors per cell, in the subcellular placement of receptor molecules, and in the cytoarchitecture of receptor-rich regions. The ability of receptors to shift between different desired states is called plasticity, and such shifts can be long-lived as well as transient. In this article we focus on neuronal receptors, although key findings from a variety of cell systems are reported. Neuronal receptor plasticity may have a special role in the assembly as well as the adaptability of the nervous system.     

Specification of neuronal identity in the embryonic CNS

One of the earliest and most crucial steps in the development of connectivity within the CNS is the acquisition of specific identities by developing neural cells. In this review, we discuss how a neural cell may come to acquire its unique identity and some of the genes that may be involved in this process. Experimental evidence suggests that ectodermal cells may pass through several phases at which their potential fates become progressively more restricted. An initial step occurs during neural induction when ectodermal cells become restricted to either a neural or non-neural fate. A little later in development, a further set of interactions determine which of the neural cells become postmitotic and begin a programme of differentiation. The differentiation phase may itself involve several steps at which the postmitotic neuron progressively advances towards its final identity.     

Cimetidine is critical in CNS disorders

There are many CNS disorders with imbalance of dopamine in brain. Cimetidine adversely increases serum level of the prolactin and leads to activate feedback control to decrease prolactin release and intensifies synthesis and secretion of dopamine. Thus, cimetidine can be critical in CNS disorders.     

The role of intrinsic neuronal properties in the encoding of auditory information in the cochlear nuclei.

It is now possible to relate the intrinsic electrical properties of particular cells in the cochlear nuclei of mammals with their biological function. In the layered dorsal cochlear nucleus, information concerning the location of a sound source seems to be contained in the spatial pattern of activation of a population of neurons. In the unlayered, ventral cochlear nucleus, however, neurons carry information in their temporal firing patterns. The voltage-sensitive conductances that make responses to synaptic current brief enable bushy cells to convey signals from the auditory nerve to the superior olivary complex with a temporal precision of at least 120 microseconds.     

Alterations in intrinsic neuronal excitability during normal aging

Normal aging subjects, including humans, have difficulty learning hippocampus-dependent tasks. For example, at least 50% of normal aging rabbits and rats fail to meet a learning criterion in trace eyeblink conditioning. Many factors may contribute to this age-related learning impairment. An important cause is the reduced intrinsic excitability observed in hippocampal pyramidal neurons from normal aging subjects, as reflected by an enlarged postburst afterhyperpolarization (AHP) and an increased spike-frequency adaptation (accommodation). In this review, we will focus on the alterations in the AHP and accommodation during learning and normal aging. We propose that age-related increases in the postburst AHP and accommodation in hippocampal pyramidal neurons play an integral role in the learning impairment observed in normal aging subjects.     

Homeostatic plasticity in the CNS: synaptic and intrinsic forms

The study of experience-dependent plasticity has been dominated by questions of how Hebbian plasticity mechanisms act during learning and development. This is unsurprising as Hebbian plasticity constitutes the most fully developed and influential model of how information is stored in neural circuits and how neural circuitry can develop without extensive genetic instructions. Yet Hebbian plasticity may not be sufficient for understanding either learning or development: the dramatic changes in synapse number and strength that can be produced by this kind of plasticity tend to threaten the stability of neural circuits. Recent work has suggested that, in addition to Hebbian plasticity, homeostatic regulatory mechanisms are active in a variety of preparations. These mechanisms alter both the synaptic connections between neurons and the intrinsic electrical properties of individual neurons, in such a way as to maintain some constancy in neuronal properties despite the changes wrought by Hebbian mechanisms. Here we review the evidence for homeostatic plasticity in the central nervous system, with special emphasis on results from cortical preparations.     

7alpha-Hydroperoxycholesterol causes CNS neuronal cell death

Brain cholesterol, which is synthesized in the central nervous system and also partly taken up from lipoproteins via the blood-brain barrier, is a major component of neuronal membranes. Oxidation of cholesterol leads to the formation of oxysterols, which have been shown to act cytotoxic. The influence of 7alpha-hydroperoxycholesterol, was investigated using the human neuroblastoma cell line SH-SY5Y. 7alpha-Hydroperoxycholesterol caused neuronal cell death; this neurotoxic effect was dose-dependent, within 48 h 10 microM led to 50%, 50 microM to 92% loss of cell viability, which was detected by cell morphology and Trypan blue exclusion. DNA-fragmentation or caspase-3 activity were not detectable, LDH release occurred rapidly and reactive oxygen species (ROS) were generated. Therefore we infer that 7alpha-hydroperoxycholesterol, apart from its role in atherosclerosis, leads to necrosis of neuronal cells.     

The neuronal progenitor cells of the forebrain subventricular zone: intrinsic properties in vitro and following transplantation

During the development of the central nervous system, progenitor cells, located within distinct germinal zones, produce presumptive neurons that migrate to their destinations and differentiate. Recent studies have demonstrated that a discrete region of the anterior part of the postnatal subventricular zone (SVZa) comprises neuronal progenitor cells whose progeny are fated to become the interneurons of the olfactory bulb. The SVZa is of particular interest because it is one of few germinal zones to persist postnatally and may be the only postnatal germinal zone to give rise exclusively to neurons. To the extent that the SVZa is unique among proliferative zones, the SVZa progeny are unique among neurons. First, unlike most cortical neurons, the SVZa-derived cells do not rely on radial glia-assisted migration when traveling to their target region. Second, the SVZa progeny continue to proliferate as they migrate to their target region. And third, the SVZa progeny express early neuron-specific antigens prior to their final division and, therefore, prior to reaching their destination where they will terminally differentiate. To better understand the capacity of the SVZa progeny to concurrently proliferate, migrate, and differentiate, we studied the cells in vitro and following transplantation into the neonatal SVZa and adult striatum. In each setting, we found that the SVZa cells continue both to proliferate and to differentiate into neurons. In addition, after homotopic and heterotopic transplantation, we found that the SVZa cells maintain their ability to migrate. These results suggest that the unique features of the SVZa progeny are specified intrinsically rather than by their extrinsic environment.     

Plasticity of the intrinsic period of the human circadian timing system

Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light ( approximately 450 lux; approximately 1.2 W/m(2)) for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration.     

SPECT neuroimaging in translational research of CNS disorders

High resolution SPECT imaging is an emerging field and there are only limited studies as yet available in this direction. Still there is continuous effort to achieve better spatial and temporal resolution in order to obtain detailed structural and functional information of different brain regions in small experimental animals. Recently, SPECT imaging system has been used to perform in vivo imaging using specific radioligands to further elucidate the role of dopaminergic, serotonergic, and cholinergic neurotransmission in relation to regional cerebral blood flow in various human CNS disorders and in gene-manipulated mouse models of neurodegeneration. Although in vivo and non-invasive translational research can be performed by high-resolution microPET imaging system, its limited spatial resolution restricts detailed anatomical and functional information of different brain regions involved in disease process. Recently developed NanoSPECT/CT imaging system has a better spatial resolution hence can be used to correlate and confirm microPET imaging data and determine the precise structural and functional anatomy of CNS disorders and their remission. Moreover SPECT imaging system reduces the cost and number of animals and provides detailed information of CNS disorders at the cellular, molecular and genetic level. Furthermore, SPECT system is economical, provides less radiation burden, and can be used to study bio-distribution of newly synthesized radioligands with increased target to non-target ratios, quality control, and clinical applications. It is envisaged that high-resolution SPECT imaging system will further improve in vivo non-invasive translational research on CNS disorders of unknown etiopathogenesis and their treatment in future.     

The role of Rho GTPase proteins in CNS neuronal migration

The architectonics of the mammalian brain arise from a remarkable range of directed cell migrations, which orchestrate the emergence of cortical neuronal layers and pattern brain circuitry. At different stages of cortical histogenesis, specific modes of cell motility are essential to the stepwise formation of cortical architecture. These movements range from interkinetic nuclear movements in the ventricular zone, to migrations of early-born, postmitotic polymorphic cells into the preplate, to the radial migration of precursors of cortical output neurons across the thickening cortical wall, and the vast, tangential migrations of interneurons from the basal forebrain into the emerging cortical layers. In all cases, actomyosin motors act in concert with cell adhesion receptor systems to provide the force and traction needed for forward movement. As key regulators of actin and microtubule cytoskeletons, cell polarity, and adhesion, the Rho GTPases play critical roles in CNS neuronal migration. This review will focus on the different types of migration in the developing neocortex and cerebellar cortex, and the role of the Rho GTPases, their regulators and effectors in these CNS migrations, with particular emphasis on their involvement in radial migration.     

Characterization of neuronal intrinsic properties and synaptic transmission in layer I of anterior cingulate cortex from adult mice

ABSTRACT: The neurons in neocortex layer I (LI) provide inhibition to the cortical networks. Despite increasing use of mice for the study of brain functions, few studies are reported about mouse LI neurons. In the present study, we characterized intrinsic properties of LI neurons of the anterior cingulate cortex (ACC), a key cortical area for sensory and cognitive functions, by using whole-cell patch clamp recording approach. Seventy one neurons in LI and 12 pyramidal neurons in LII/III were recorded. Although all the LI neurons expressed continuous adapting firing characteristics, the unsupervised clustering results revealed five groups in the ACC, including: Spontaneous firing neurons; Delay-sAHP neurons, Delay-fAHP neurons, and two groups of neurons with ADP , ADP1 and ADP2. Using pharmacological approaches, we found that LI neurons receive both excitatory (mediated by AMPA, kainate and NMDA receptors), and inhibitory inputs (which were mediated by GABAA receptors). Our studies provide the first report characterizing the electrophysiological properties of neurons in LI of the ACC from adult mice.     

Ca2+ transients control CNS neuronal migration

In the developing CNS, postmitotic neurons exhibit dynamic changes in the mode, direction and rate of migration as they traverse different cortical layers, but the mechanisms underlying this process is largely unknown. Recent studies show that the changes in Ca2+ transient frequency play a central role in controlling the neuronal cell migration in a cortical layer-specific manner. In this article, we will first describe how granule cells migrate through different terrains of the developing cerebellar cortex. We will then present how such migration of granule cells is controlled by altering the Ca2+ transient frequency in their somata. Finally, we will discuss how the loss of Ca2+ transients triggers the completion of granule cell migration at their final destination.     

Plasticity of neuronal excitability: Hebbian rules beyond the synapse

Activity-dependent synaptic plasticity is classically though to be the cellular substrate for learning and memory. Recent data show that activation of glutamate receptors initiates a long-term modification in pre- or post-synaptic neuronal excitability. Similarly to synaptic plasticity, intrinsic plasticity is bidirectional and input- or cell-specific. In addition to an increase in the reliability of the input-output function, temporal precision of the neuronal discharge is improved. These forms of plasticity not only share common learning rules and induction pathways with the better known synaptic plasticity but may also contribute in synergy with these synaptic changes to the formation of a coherent mnesic engram.     

Maintaining the neuronal phenotype after injury in the adult CNS

Multiple genetic and epigenetic events determine neuronal phenotype during nervous system development. After the mature mammalian neuronal phenotype has been determined it is usually static for the remainder of life, unless an injury or degenerative event occurs. Injured neurons may suffer one of three potential fates: death, persistent atrophy, or recovery. The ability of an injured adult neuron to recover from injury in adulthood may be determined by events that also influence neuronal phenotype during development, including expression of growth-related genes and responsiveness to survival and growth signals in the environment. The latter signals include neurotrophic factors and substrate molecules that promote neurite growth. Several adult CNS regions exhibit neurotrophic-factor responsiveness, including the basal forebrain, entorhinal cortex, hippocampus, thalamus, brainstem, and spinal cord. The specificity of neurotrophic-factor responsiveness in these regions parallels patterns observed during development. In addition, neurons of several CNS regions extend neurites after injury when presented with growth-promoting substrates. Whenboth neurotrophic factors and growth-promoting substrates are provided to adult rats that have undergone bilateral fimbria-fornix lesions, then partial morphological and behavioral recovery can be induced. Gene therapy is one useful tool for providing these substances. Thus, the mature CNS remains robustly responsive to signals that shape nervous system development, and is highly plastic when stimulated by appropriate cues.     

The Involvement of the Myelin-Associated Inhibitors and Their Receptors in CNS Plasticity and Injury

The limited capacity for the central nervous system (CNS) to repair itself was first described over 100 years ago by Spanish neuroscientist Ramon Y. Cajal. However, the exact mechanisms underlying this failure in neuronal regeneration remain unclear and, as such, no effective therapeutics yet exist. Numerous studies have attempted to elucidate the biochemical and molecular mechanisms that inhibit neuronal repair with increasing evidence suggesting that several inhibitory factors and repulsive guidance cues active during development actually persist into adulthood and may be contributing to the inhibition of repair. For example, in the injured adult CNS, there are various inhibitory factors that impede the outgrowth of neurites from damaged neurons. One of the most potent of these neurite outgrowth inhibitors is the group of proteins known as the myelin-associated inhibitors (MAIs), present mainly on the membranes of oligodendroglia. Several studies have shown that interfering with these proteins can have positive outcomes in CNS injury models by promoting neurite outgrowth and improving functional recovery. As such, the MAIs, their receptors, and downstream effectors are valid drug targets for the treatment of CNS injury. This review will discuss the current literature on MAIs in the context of CNS development, plasticity, and injury. Molecules that interfere with the MAIs and their receptors as potential candidates for the treatment of CNS injury will additionally be introduced in the context of preclinical and clinical trials.