The PSA-NCAM-Positive “Immature” Neurons: An Old Discovery Providing New Vistas on Brain Structural Plasticity

Abstract

Studies on brain plasticity have undertaken different roads, tackling a wide range of biological processes: from small synaptic changes affecting the contacts among neurons at the very tip of their processes, to birth, differentiation, and integration of new neurons (adult neurogenesis). Stem cell-driven adult neurogenesis is an exception in the substantially static mammalian brain, yet, it has dominated the research in neurodevelopmental biology during the last thirty years. Studies of comparative neuroplasticity have revealed that neurogenic processes are reduced in large-brained mammals, including humans. On the other hand, large-brained mammals, with respect to rodents, host large populations of special “immature” neurons that are generated prenatally but express immature markers in adulthood. The history of these “immature” neurons started from studies on adhesion molecules carried out at the beginning of the nineties. The identity of these neurons as “stand by” cells “frozen” in a state of immaturity remained un-detected for long time, because of their ill-defined features and because clouded by research ef-forts focused on adult neurogenesis. In this review article, the history of these cells will be reconstructed, and a series of nuances and confounding factors that have hindered the distinction between newly generated and “immature” neurons will be addressed.

Autoantibodies against NCAM1 from patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice

“…The polysialylated form of NCAM1 (PSA-NCAM) is abundant during developmental stages in the nervous system and is associated with cell migration and axonal growth. 29 Polysialylation occurs on the Ig5 domain of NCAM1. 30 , 31 Thus, we hypothesized that anti-NCAM1 autoantibodies also detect PSA-NCAM.…”

How Widespread Are the “Young” Neurons of the Mammalian Brain?

“…These cells were firstly described in the piriform cortex layer II ( Seki and Arai, 1991 ; Bonfanti et al, 1992 ), and are currently (provisionally) referred to as “immature” or “dormant” neurons, since they are generated pre-natally, then remaining in a “standby” state of immaturity for long time ( Luzzati et al, 2009 ; Gómez-Climent et al, 2008 ; Klempin et al, 2011 ; Bonfanti and Nacher, 2012 ; König et al, 2016 ; Rotheneichner et al, 2018 ; Benedetti and Couillard-Després, 2022 ). This idea of “young,” non-dividing neurons has evolved slowly through the years, somehow overwhelmed by the emphasis focused on adult neurogenesis ( Bonfanti and Seki, 2021 ). These neurons can re-activate their maturational process to finally mature and integrate into adult circuits ( Rotheneichner et al, 2018 ; Benedetti et al, 2020 ).…”

“…At present, this is only an hypothesis that should be verified with systematic, quantitative interspecies analyses, similarly to those carried out in the cortex ( La Rosa et al, 2020b ). Very few is known regarding the real nature/origin of the subcortical DCX + cells, sometimes interpreted as newly generated in the past ( Table 1 ), when DCX was considered a proxy for neurogenesis ( Bonfanti and Seki, 2021 ). Taking into account that such neurons seem to be important in primates (references in Table 1 ), the use of experimental approaches aimed at establishing their origin are far from easy.…”

“…The new neurons born in stem cell niches and integrating into pre-existing neural circuits, generated controversies for decades due to a mix of conterintuitive novelty and objective technical difficulties ( Kaplan, 2001 ). Then, a sort of confusion continued (and continues) to characterize this fascinating research field ( Lipp and Bonfanti, 2016 ; Parolisi et al, 2018 ; Duque and Spector, 2019 ; Petrik and Encinas, 2019 ; Bonfanti and Seki, 2021 ; Duque et al, 2022 ), especially concerning its existence/rate in adult humans ( Sanai et al, 2011 ; Moreno-Jiménez et al, 2021 ; Sorrells et al, 2021 ) and the putative occurrence of non-canonical neurogenesis within parenchymal brain regions ( Bonfanti and Peretto, 2011 ; Feliciano et al, 2015 ). A major unresolved point is the occurrence of “young,” immature neurons in the adult brain, in the absence or very low levels of cell division ( Moreno-Jimenéz et al, 2019 ; Sorrells et al, 2018 , 2019 ).…”

Polysialic Acid Sustains the Hypoxia-Induced Migration and Undifferentiated State of Human Glioblastoma Cells

“…In the adult brain, PSA is mainly observed in those brain regions where neurogenesis persists, namely sub-ventricular zone (SVZ), sub-granular zone (SGZ) and olfactory bulbs (OB) [ 13 ]. The polysialylated form of NCAM plays an important role in neural development, being involved in cell migration [ 14 ], synaptic plasticity [ 15 , 16 ] and neurite outgrowth [ 17 ]. NCAM undergoes post-translational modifications being polysialylated by two polysialyltransferases (PolySTs) in the Golgi, STX (ST8SiaII), and PST (ST8SiaIV) [ 18 ].…”