Cholinergic regulation of cortical development and plasticity - New twiststo an old story

Cholinergic afferents innervate cerebral cortex during the most dynamic per iod of neuronal differentiation and synapse formation, suggesting they play a possible regulatory role in these events. A number of in vivo studies ha ve shown over the last decade that alterations in cholinergic innervation d uring early postnatal development can change various features of cortical o ntogeny. In particular, neonatal lesions to basal forebrain cholinergic aff erents result in delayed cortical neuronal development and permanently alte red cortical cytoarchitecture and cognitive behaviors. Likewise, cholinergi c manipulations affect morphological plasticity in cat visual cortex as wel l as in the somatosensory cortex of rodents. Furthermore, augmentation of c holinergic function by means of perinatal choline treatment enhances cognit ive performance in a sex specific manner. Additional indications for a sexu al dimorphism in cortical cholinergic innervation and resulting function ar e gathered from a variety of paradigms. Recent information about effects of NGF, BDNF and NTB-4/5 on cortical morphogenesis and plasticity reveals com plex interactions between the cholinergic basal forebrain afferents and thi s neurotrophin family. Detailed studies on the expression of cholinergic re ceptor proteins in cortical development and their associated signal transdu ction pathways strongly point towards a morphogenetic function of muscarini c receptors, in particular. Transient receptor localization in thalamocorti cal terminal fields and on a variety of other non-cholinergic fiber bundles suggest a cholinergic role in target finding and/or synapse formation for cortical afferents and efferents. We propose a hypothesis regarding the mec hanisms for cholinergic regulation of neuronal differentiation and synapse formation on the level of the individual growth cone and discuss possibilit ies for cholinergic interactions with differential gene expression. We conc lude that understanding the precise role of the cholinergic system in corti cal morphogenesis and its relationship to neurotrophin function will be of clinical relevance for a number of developmental brain disorders, including Down Syndrome and Rett Syndrome.