The neuropeptide galanin is expressed developmentally in the dorsal root ganglion (DRG) and is rapidly up-regulated 120-fold after peripheral nerve section in the adult. Here we report that adult mice carrying a loss-of-function mutation in the galanin gene have a 13% reduction in the number of cells in the DRG associated with a 24% decrease in the percentage of neurons that express substance P. These deficits are associated with a 2.8-and 2.6-fold increase in the number of apoptotic cells in the DRG at postnatal days 3 and 4, respectively. After crush injury to the sciatic nerve, the rate of peripheral nerve regeneration is reduced by 35% with associated long-term functional deficits. Cultured DRG neurons from adult mutant mice demonstrate similar deficits in neurite number and length. These results identify a critical role for galanin in the development and regeneration of sensory neurons. D amage to a peripheral nerve causes changes within the cell body that promote neuronal survival, axonal regeneration, and functional recovery. Under favorable conditions, for instance after a crush injury, most nerve fibers successfully regenerate. However, in many clinically relevant circumstances, traumatic or disease-induced nerve injury has a poor outcome with only limited return of function and often with considerable delay. The molecular and cellular interactions that control the degree and rate of peripheral nerve regeneration are poorly understood and remain important clinical and scientific issues.In an attempt to define the mechanisms that regulate neuronal survival and regeneration, we and others have used the approach of studying factors whose expression patterns are known to change in response to injury. One of the most potent changes in the dorsal root ganglion (DRG) after peripheral nerve injury is the 120-fold increase in the levels of the 29-aa neuropeptide galanin (1). Studies have demonstrated that galanin is expressed at high levels in most cells of the developing DRG from day 16 of gestation until shortly after birth (2). In the adult, galanin is expressed at low levels in only 2-3% of DRG cells, which are predominantly small fiber neurons (1). After axotomy, mRNA and peptide are abundantly expressed in 40-50% of all DRG neurons (3) and remain elevated while the nerve is regenerating (1). Similarly, axotomy also up-regulates galanin expression in motor (4) and sympathetic (5) neurons. The rise in expression in the dorsal horn after axotomy is modest compared with the marked elevation in the DRG (6), reflecting an increase in anterograde transport of galanin from the cell body to the site of injury (7), analogous to that described in axotomized sympathetic neurons (8). Despite these findings, there is no direct evidence that galanin plays a role in axonal regeneration after injury.We previously have generated mice carrying a loss-of-function mutation in the galanin gene (9) and most recently have demonstrated that the chronic absence of galanin throughout prenatal and postnatal development causes an atte...

The neuropeptide galanin colocalizes with choline acetyltransferase, the synthetic enzyme for acetylcholine, in a subset of cholinergic neurons in the basal forebrain of rodents. Chronic intracerebroventricular infusion of nerve growth factor induces a 3-to 4-fold increase in galanin gene expression in these neurons. Here we report the loss of a third of cholinergic neurons in the medial septum and vertical limb diagonal band of the basal forebrain of adult mice carrying a targeted loss-of-function mutation in the galanin gene. These deficits are associated with a 2-fold increase in the number of apoptotic cells in the forebrain at postnatal day seven. This loss is associated with marked agedependent deficits in stimulated acetylcholine release, performance in the Morris water maze, and induction of long-term potentiation in the CA1 region of the hippocampus. These data provide unexpected evidence that galanin plays a trophic role to regulate the development and function of a subset of septohippocampal cholinergic neurons.T he 29 amino acid peptide galanin (1) colocalizes with choline acetyltransferase (ChAT) in 30-35% of cholinergic neurons in the medial septum and vertical limb diagonal band (VLDB) of the basal forebrain in the rat (2, 3). Most, if not all, of these galaninpositive cholinergic neurons project to the hippocampus (2, 4). These findings have led to a number of functional studies addressing the role played by galanin in the basal forebrain cholinergic system, including its effects on acetylcholine (ACh) release as well as learning and memory. Acute administration of galanin into the hippocampus or third ventricle of rodents inhibits scopolamineinduced ACh release in a dose-dependent manner and is reversed by the coadministration of the chimeric-peptide galanin receptor antagonists M15 and M40 (5, 6). Centrally administered galanin also has inhibitory effects on several tests of learning and memory (7,8). In contrast to these inhibitory actions, exogenous galanin has no effect on the increased release of ACh that occurs when a rodent is exposed to a novel environment (9). Neither of the galanin antagonists has an effect on ACh release or on cognition in the absence of exogenously administered galanin (5, 6). Similarly, whereas exogenous galanin inhibits long-term potentiation (LTP) in hippocampal CA1 slices that is reversed by the M40 galanin antagonist, M40 has no effect on LTP when applied alone (10). In addition, there is increasing evidence that the M15 and M40 ligands may act as partial agonists in the hippocampus (11, 12) and as full agonists in vitro to the cloned galanin receptor subtypes (13). These somewhat conflicting data emphasize the limitations of the pharmacological tools that are currently available and cast some doubt on the role played by endogenously secreted galanin in the modulation of steady-state ACh release.We have recently generated mice carrying a loss-of-function mutation in the galanin gene (14) and have demonstrated that galanin is (i) essential for the developmental s...

The 29 amino acid neuropeptide galanin is normally expressed in < 5% of sensory neurons in the adult dorsal root ganglia. After nerve transection (axotomy), the galanin content of the dorsal root ganglia rises 120-fold and the peptide is then expressed in > 50% of neurons. Published data suggest that galanin plays a role in the modulation of pain processing and may be involved in the regeneration of sensory neurons. Here we describe the initial characterisation of a new line of transgenic mice that selectively over-express galanin in the dorsal root ganglia in an inducible manner following axotomy of the sciatic nerve, but not in the uninjured state. Results of acute thermal or mechanosensory pain tests are normal in intact transgenic animals when compared to wild-type controls. The generation of these novel transgenic animals will be most useful as genetic tools to further elucidate the role played by galanin in the adaptive response of the peripheral nervous system to injury.