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This chapter describes recent progress in the understanding of the regulation of neurotrophin and neurotrophin receptor expression in the hippocampal formation following pharmacological manipulations or brain lesions. The chapter is subdivided into different sections which provide details about five different pharmacological treatment regimens and lesion paradigms found to influence neurotrophin mechanisms.

Brain derived neurotrophic factor (BDNF) is a 13.5 kD polypeptide related to nerve growth factor (NGF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4), (for review see Lapchak et al., this volume), and which has been shown to promote the survival and differentiation of in vitro neuronal populations (Davies et al., 1986; Johnson et al., 1986; Alderson et al., 1990; Hyman et al., 1990; Knusel et al., 1990). Similar to NGF and NT3, BDNF mRNA is expressed in the target regions of the basal forebrain cholinergic system, with highest levels occurring in the hippocampal pyramidal, hilar and granule subregions (Hofer et al., 1990; Phillips et al., 1990; Wetmore et al., 1990; Dugich-Djordjevic et al., 1991a). Moreover, the expression of BDNF mRNA is localized to neuronal cell populations in hippocampal subregions (Wetmore et al., 1990; Dugich-Djordjevic et al., 1991a), and a possible localization to the neuropil in certain brain regions has been suggested (Dugich-Djordjevic et al., 1991b).

Nerve growth factor (NGF) promotes the maintenance of function and survival of adult cholinergic neurons of the septo-hippocampal pathway and attenuates lesion-induced deficits in neurochemical and behavioral measures related to cholinergic septo-hippocampal functions (Hefti et al., 1984; Will and Hefti, 1985; Williams et al, 1986, 1989; Will et al., 1988, 1990; Lapchak and Hefti, 1991).

The neurotrophins represent a family of polypeptide growth factors which show a high degree of homology with nerve growth factor (NGF). Recent investigations by various research groups have resulted in the isolation, purification and cloning of three novel neurotrophins:brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4). The present review is intended to provide a brief overview of the principal characteristics and roles of the neurotrophins and their receptors in the mammalian central nervous system (CNS). The neurotrophin family of growth factors may prove to be of considerable importance in the future therapy of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases.

Alzheimer’s disease (AD) is characterized by an exten­sive degeneration of the cholinergic system in the human nucleus basalis of Meynert, neocortex and hippocampus (1–5), mainly based upon measures of choline acetyltransferase act­ivity (ChAT). Cholinergic receptor populations (muscarinic and nicotinic) have also been studied in Alzheimer’s disease; however the results of studies concerning muscarinic recep­tors are variable and inconsistent (1, 6–8). The variability may be due to the non-selective nature of the ligands used to measure muscarinic receptor populations. Alternatively, the discrepancy may be explained by the existence of multiple subtypes of muscarinic receptors in the CNS (see 5). Muscarinic receptors can be subdivided into a number of subtypes (M1–M3) which may be selectively labeled using 3H-pirenzepine (M1), 3H-ACh or 3H-AF-DX 116 (M2), or 3H-4DAMP (M3) (5, 9–12) In contrast to muscarinic receptors, results concerning the fate of neuronal nicotinic receptor populations in AD cortex are more consistent. These studies indicate that the density of nicotinic receptors, at least in cortical structures, is severely reduced in AD (3,5,13,14). It is essential to de­termine whether specific cholinergic receptor populations are affected in various regions of the AD brain in order to develop a strategy for the treatment of AD.

The localization of various growth factors (GFs) and lymphokines in the mammalian brain (1) has expanded the list of possible roles for these substances. The identification of specific binding sites for GFs such as nerve GF (NGF), epidermal GF(EGF), and the insulin-like GFs (IGF-1 and IGF-2) (2), and for IL-1 (3–5), on cells of glial and neuronal origin have underlined further the importance of GFs and ILs in the mammalian CNS. However, the precise function of these substances in the brain has not been completely elucidated.