Abstract
Modulation of endogenous neurogenesis is regarded as a promising challenge in neuroprotection. In the rat model of hippocampal neurodegeneration obtained by Trimethyltin (TMT) administration (8 mg/kg), characterised by selective pyramidal cell loss, enhanced neurogenesis, seizures and cognitive impairment, we previously demonstrated a proliferative role of exogenous neuropeptide Y (NPY), on dentate progenitors in the early phases of neurodegeneration. To investigate the functional integration of newly-born neurons, here we studied in adult rats the long-term effects of intracerebroventricular administration of NPY (2 µg/2 µl, 4 days after TMT-treatment), which plays an adjuvant role in neurodegeneration and epilepsy. Our results indicate that 30 days after NPY administration the number of new neurons was still higher in TMT+NPY-treated rats than in control+saline group. As a functional correlate of the integration of new neurons into the hippocampal network, long-term potentiation recorded in Dentate Gyrus (DG) in the absence of GABAA receptor blockade was higher in the TMT+NPY-treated group than in all other groups. Furthermore, qPCR analysis of Kruppel-like factor 9, a transcription factor essential for late-phase maturation of neurons in the DG, and of the cyclin-dependent kinase 5, critically involved in the maturation and dendrite extension of newly-born neurons, revealed a significant up-regulation of both genes in TMT+NPY-treated rats compared with all other groups. To explore the early molecular events activated by NPY administration, the Sonic Hedgehog (Shh) signalling pathway, which participates in the maintenance of the neurogenic hippocampal niche, was evaluated by qPCR 1, 3 and 5 days after NPY-treatment. An early significant up-regulation of Shh expression was detected in TMT+NPY-treated rats compared with all other groups, associated with a modulation of downstream genes. Our data indicate that the neurogenic effect of NPY administration during TMT-induced neurodegeneration involves early Shh pathway activation and results in a functional integration of newly-generated neurons into the local circuit.
Highlights
Hippocampal neurogenesis is a highly regulated process which, throughout adult mammalian life, generates new cells differentiating into functionally integrated granular neurons
Since the early molecular events triggered by neuropeptide Y (NPY) administration and mediating its neurogenic effect have not been definitively clarified, in the present study we explored the possible role of molecular pathways critically involved in the establishment and maintenance of the adult hippocampal neurogenic niche, such as that involving Sonic Hedgehog (Shh) signalling
To assess the functional integration of newly-born neurons into the dentate gyrus (DG) network, we studied long-term potentiation (LTP) at the medial perforant path (MPP)-dentate granule cell (DGC) synapses in slices from rats belonging to the four experimental groups perfused with normal artificial cerebrospinal fluid (aCSF), i.e., without GABAA receptor antagonists. aCSF-LTP is fairly weak compared to that usually recorded in the presence of GABAA receptor blockers, but the potentiation that is observed can be attributed to the newlygenerated neurons [60,61]
Summary
Hippocampal neurogenesis is a highly regulated process which, throughout adult mammalian life, generates new cells differentiating into functionally integrated granular neurons As this form of brain plasticity can be influenced by endogenous and exogenous factors, as well as by pathological conditions [1,2,3] including neurodegenerative diseases and epilepsy [1,4], the modulation of adult neurogenesis constitutes an attractive research field. The pharmacological targeting of endogenous mechanisms may offer clues useful to the development of novel therapeutic strategies in the damaged brain In this regard, recent evidence largely supports the involvement of neuropeptide Y (NPY) in the modulation of endogenous neurogenesis [5,6,7]. This effect appears to be mediated by the Y1 receptors, and to involve the ERK1/2 signalling pathway [9] and is restricted to nestin, beta tubulin and doublecortin-expressing progenitors [9,13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
