Discerning Neurogenic vs. Non-Neurogenic Postnatal Lateral Ventricular Astrocytes via Activity-Dependent Input

Abstract

Throughout development, neural stem cells (NSCs) give rise to differentiated neurons, astrocytes, and oligodendrocytes which together modulate perception, memory, and behavior in the adult nervous system. To understand how NSCs contribute to postnatal/adult brain remodeling and repair after injury, the lateral ventricular (LV) neurogenic niche in the rodent postnatal brain serves as an excellent model system. It is a specialized area containing self-renewing GFAP+ astrocytes functioning as NSCs generating new neurons throughout life. In addition to this now well-studied regenerative process, the LV niche also generates differentiated astrocytes, playing an important role for glial scar formation after cortical injury. While LV NSCs can be clearly distinguished from their neuroblast and oligodendrocyte progeny via molecular markers, the astrocytic identity of NSCs has complicated their distinction from terminally-differentiated astrocytes in the niche. Our current models of postnatal/adult LV neurogenesis do not take into account local astrogenesis, or the possibility that cellular markers may be similar between non-dividing GFAP+ NSCs and their differentiated astrocyte daughters. Postnatal LV neurogenesis is regulated by NSC-intrinsic mechanisms interacting with extracellular/niche-driven cues. It is generally believed that these local effects are responsible for sustaining neurogenesis, though behavioral paradigms and disease states have suggested possibilities for neural circuit-level modulation. With recent experimental findings that neuronal stimulation can directly evoke responses in LV NSCs, it is possible that this exciting property will add a new dimension to identifying postnatal/adult NSCs. Here, we put forth a notion that neural circuit-level input can be a distinct characteristic defining postnatal/adult NSCs from non-neurogenic astroglia.

Nigrostriatal interaction in the aging brain: new therapeutic target for Parkinson’s disease

“…Axons of this pathway synapse onto GABAergic striatal medium spiny neurons (MSNs) and thus gain access to the main functions of motor control. This unique synaptic junction between the GABAergic and dopaminergic systems, results in a close and specific functional interaction between both systems, including the process of nigrostriatal synaptogenesis and continuous cellular turnover of striatal interneurons (Dayer et al 2005, Curtis et al 2011, Ernst et al 2014, Adlaf et al 2016. Consequently, the motor symptoms of Parkinson's disease may be due both to the dysfunction of dopaminergic SNpc or to the GABAergic striatum.…”

“…In contrast to the medium spiny projection neurons, the GABA interneurons and their supportive, non-neuronal cells (a subset of short-lived oligodendrocytes), are prone to neurodegeneration (Ernst et al 2014). However, lost interneurons and oligodendycytes are constantly replaced with new ones in the process of striatal cell turnover (Bédard et al 2002, Brazel et al 2003, Dayer et al 2005, Ernst et al 2014, Adlaf et al 2016. In humans, the subventricular zone (SVZ) is a specialized area containing self-renewing GFAP+ astrocytes functioning as neural stem cells that generate new GABA fast-spiking interneurons in the striatum throughout life (Brazel et al 2003, Adlaf et al 2016).…”

“…However, lost interneurons and oligodendycytes are constantly replaced with new ones in the process of striatal cell turnover (Bédard et al 2002, Brazel et al 2003, Dayer et al 2005, Ernst et al 2014, Adlaf et al 2016. In humans, the subventricular zone (SVZ) is a specialized area containing self-renewing GFAP+ astrocytes functioning as neural stem cells that generate new GABA fast-spiking interneurons in the striatum throughout life (Brazel et al 2003, Adlaf et al 2016). In the adult human striatum, the median turnover rate of interneurons is comparable to the turnover rate of neurons within the hippocampus (Ernst et al 2014).…”

“…Importantly, it seems well-documented that cytokines from apoptotic neurons may initiate the process of striatal cell turnover. Thus, an increased SVZ proliferation follows striatal neuron death (Brazel et al 2003, Adlaf et al 2016). In the other words, neurodegeneration of striatal GABA interneurons initiates neurogenesis that compensates for the loss of fast-firing interneurons.…”

“…It has been shown recently that the neural stem cells within the striatum respond directly to GABA (Adlaf et al 2016). Consequently, inserting glutamic acid decarboxylase (GAD) gene into the subthalamic nucleus seems to offer an alternative therapeutic strategy (LeWitt et al 2011).…”