Regulation Of Microtubule: Current Concepts And Relevance To Neurodegenerative Diseases

: Neurodevelopmental disorders (NDDs) are abnormalities linked to neuronal structure and irregularities associated with the proliferation of cells, transportation, and differentiation. NDD also involves synaptic circuitry and neural network alterations known as synaptopathies. Microtubules (MTs) and MTs-associated proteins help to maintain neuronal health as well as their development. The microtubular dynamic structure plays a crucial role in the division of cells and forms mitotic spindles, thus take part in initiating stages of differentiation and polarization for various types of cells. The MTs also take part in the cellular death but MT-based cellular degenerations are not yet well excavated. In the last few years, studies have provided the protagonist activity of MTs in neuronal degeneration. In this review, we largely engrossed our discussion on the change of MT cytoskeleton structure, describing their organization, dynamics, transportation, and their failure causing NDDs. At end of this review, we are targeting the therapeutic neuroprotective strategies on clinical priority and also try to discuss the clues for the development of new MT-based therapy as a new pharmacological intervention. This will be a new potential site to block not only neurodegeneration but also promotes the regeneration of neurons.

Control of neurogenic competence in mammalian hypothalamic tanycytes

Hypothalamic tanycytes, radial glial cells that share many features with neuronal progenitors, generate small numbers of neurons in the postnatal hypothalamus, but the identity of these neurons and the molecular mechanisms that control tanycyte-derived neurogenesis are unknown. In this study, we demonstrate that tanycyte-specific disruption of the NFI family of transcription factors (Nfia/b/x) robustly stimulates tanycyte proliferation and tanycyte-derived neurogenesis. Single-cell RNA- and ATAC-Seq analysis reveals that NFI factors repress Shh and Wnt signaling in tanycytes, and small molecule modulation of these pathways blocks proliferation and tanycyte-derived neurogenesis in Nfia/b/x-deficient mice. We show that Nfia/b/x-deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, integrate into hypothalamic synaptic circuitry, and selectively respond to changes in internal states. These findings identify molecular mechanisms that control tanycyte-derived neurogenesis, suggesting a new therapeutic approach to selectively remodel the hypothalamic neural circuitry that controls homeostatic physiological processes.

Learning excitatory-inhibitory neuronal assemblies in recurrent networks

In sensory circuits with poor feature topography, stimulus-specific feedback inhibition necessitates carefully tuned synaptic circuitry. Recent experimental data from mouse primary visual cortex (V1) show that synapses between pyramidal neurons and parvalbumin-expressing (PV) inhibitory interneurons tend to be stronger for neurons that respond to similar stimulus features. The mechanism that underlies the formation of such excitatory-inhibitory (E/I) assemblies is unresolved. Here, we show that activity-dependent synaptic plasticity on input and output synapses of PV interneurons generates a circuit structure that is consistent with mouse V1. Using a computational model, we show that both forms of plasticity must act synergistically to form the observed E/I assemblies. Once established, these assemblies produce a stimulus-specific competition between pyramidal neurons. Our model suggests that activity-dependent plasticity can enable inhibitory circuits to actively shape cortical computations.

Kainate receptors regulate development of glutamatergic synaptic circuitry in the rodent amygdala

Perturbed information processing in the amygdala has been implicated in developmentally originating neuropsychiatric disorders. However, little is known on the mechanisms that guide formation and refinement of intrinsic connections between amygdaloid nuclei. We demonstrate that in rodents the glutamatergic connection from basolateral to central amygdala (BLA-CeA) develops rapidly during the first 10 postnatal days, before external inputs underlying amygdala-dependent behaviors emerge. During this restricted period of synaptic development, kainate-type of ionotropic glutamate receptors (KARs) are highly expressed in the BLA and tonically activated to regulate glutamate release via a G-protein-dependent mechanism. Genetic manipulation of this endogenous KAR activity locally in the newborn LA perturbed development of glutamatergic input to CeA, identifying KARs as a physiological mechanism regulating formation of the glutamatergic circuitry in the amygdala.

p75NTR as a Molecular Memory Switch

In recent years, many molecular and environmental factors have been studied to understand how synaptic plasticity is modulated. Sleep, as an evolutionary conserved biological function, has shown to be a critical player for the consolidation and filtering of synaptic circuitry underlying memory traces. Although sleep disturbances do not alter normal memory consolidation, they may reflect fundamental circuit malfunctions that can play a significant role in exacerbating diseases, such as autism and Alzheimer’s disease. Very recently, scientists sought to answer part of this enigma and they identified p75 neurotrophic receptor (p75NTR) as a critical player in mediating impairments in hippocampal-dependent associative plasticity upon sleep deprivation. This paper will review the role of the p75NTR, critically discuss the impact and implications of this research as the bridge for sleep research and neurological diseases.

Area postrema: fetal maturation, tumours, vomiting centre, somatic growth and role in neuromyelitis optica

The area postrema (AP) in the caudal 4th ventricular floor is unique, highly vascular without blood/brain or /CSF barrier. In addition to its function as the vomiting centre, several other important functions are: part of the circumventricular organs for vasomotor and angiotensin II regulation; a role in neuromyelitis optica related to aquaporin-4; contributor to fetal and postnatal somatic growth. Functions are immature at birth.The purpose of this study was to demonstrate AP neuronal/synaptic/glial maturation in normal fetuses and 3 AP tumours. Transverse sections of the caudal 4th ventricle of 18 normal human fetal brains at autopsy, 6 to 40 weeks were examined; also 3 infants 3-18mos; 2 children. A battery of immunocytochemical neuronal and glial markers: MAP2; calretinin; synaptophysin; vimentin; nestin; GFAP; S-100β protein; were applied to paraffin sections. Two children with AP tumours and one with neurocutaneous melanocytosis, all with pernicious vomiting, were studied. In normal fetuses, AP neurons exhibited cytological maturity and well-formed synaptic circuitry by 14wk gestation. Size/volume increase was disproportionately greater than brainstem growth in 2nd and 3rd trimesters and postnatally. Astrocytes co-expressed vimentin/GFAP but glia were best demonstrated by S-100β protein. Ependyma over the AP in fetuses is simple cuboidal, adjacent to pseudostratified columnar of the 4th ventricular floor. Melanocytes infiltrated AP in the toddler with pernicious vomiting; 2 children had primary AP pilocytic astrocytomas. Though AP is cytologically mature by 14wk, growth increases and functions mature into the postnatal months. We recommend that AP neuropathology include synaptophysin and S-100β at autopsy if AP dysfunction suspected.LEARNING OBJECTIVESThis presentation will enable the learner to:1.Explain the maturation of neurons, synaptic circuits and glial elements of the AP2.List and recognize tumours that can affect the area postrema3.Describe functions of the area postrema