95et al. 2014 ). Recently, cholinergic stimulation was shown to control the response of
SEZ cells to experimental stroke (Wang et al. 2017 ). Serotonergic axons had been
identified near the walls of the ventricles since the late 90’s, described also to be in
close association with ependymal cells (Mathew 1999 ). These observations were
confirmed recently and serotonin receptors 2C and 5A were found to be expressed
by type B cells. The intracerebroventricular infusion of 2C agonists and antagonists
altered the proliferation of NSCs in the SEZ (Tong et al. 2014a) and the chronic
activation of 1A and 2C receptors induced proliferation in the olfactory bulbs
(Soumier et al. 2010 ).
Finally, the best described neurotransmitter to have a role in regulating neuro-
genesis in the SEZ is gamma-amino butyric acid (GABA). In the postnatal SEZ,
young neuroblasts spontaneously release GABA, which activates GABAα receptors
and depolarizes precursor cells resulting in the inhibition of cell proliferation and
neuronal differentiation through the recruitment of the PI3K-related kinase signal-
ing pathway and histone H2AX phosphorylation. Surprisingly, these changes can
lead to long-lasting changes in stem cell numbers, the niche size, and neuronal
output (Fernando et al. 2011 ). A year later a negative-feedback mechanism with
which neuroblasts restrict their own production was described to involve GABAergic
inhibition (Alfonso et al. 2012 ), since type B and C cells were shown to secrete the
diazepam-binding inhibitor protein (DBI) which acts as a positive modulator of
SEZ postnatal proliferation and neurogenesis by competitively inhibiting GABA
binding to its receptors. Subsequently, the existence of significant heterogeneity in
regard to GABA receptor subunit composition throughout the human SEZ was
found (Dieriks et al. 2013 ). For example, expression of GABA(A)R α 2 and γ 2 units
was specifically detected on cells proximal to large SEZ BVs, where the SEZ was
much thicker.
6.3.2 In the Subgranular Zone (SGZ)
The neurogenic region of the hippocampus is restricted to the subranular zone
(SGZ) close to the dentate gyrus (Kazanis 2012 , 2013 ). Similarly to the SEZ, the
SGZ is characterized by the existence of relatively quiescent NSCs of astroglial
morphology that generate precursors of neuronal commitment (neuroblasts) which
migrate to their target area in the granule neuron layers to differentiate in mature
neurons, which integrate in an already existent neuronal network. The neurogenic
system of the SGZ does not form an anatomically separate structure. However,
NSCs are confined in a restricted area, surrounded by intermediate progenitors,
astrocytes, mature granule cells and blood vessels; thus, the SGZ is also referred to
as a stem cell niche (Palmer et al. 2000 ) (Fig. 6.2b). In the SGZ the number of cells
being produced is smaller compared to that of the SEZ (Kazanis 2013 ), but their
function is significantly different as they contribute to processes such as memory
and learning. This is why impaired neurogenesis has been linked to the development
of mental health and cognitive disorders (Aimone et al. 2011 ; Noonan et al. 2010 ;
Sahay et al. 2011 ).
6 Being a Neural Stem Cell: A Matter of Character But Defined...