Galanin regulates the postnatal survival of a subset of basal forebrain cholinergic neurons

Abstract

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...

Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin

“…Galanin-binding sites have been mapped (7,8), and three receptor subtypes, GalR1 (9-11), GalR2 (12)(13)(14)49), and GalR3 (15), have been cloned. There is evidence for involvement of galanin in multiple neuronal functions (16,17), as also revealed in recent studies on transgenic mice (18)(19)(20).…”

“…Galanin-binding sites have been mapped (7,8), and three receptor subtypes, GalR1 (9-11), 49), and GalR3 (15), have been cloned. There is evidence for involvement of galanin in multiple neuronal functions (16,17), as also revealed in recent studies on transgenic mice (18)(19)(20).Many studies support an important role of neuropeptides in seizure activity (21)(22)(23). This role is true also for galanin.…”

The neuropeptide galanin modulates behavioral and neurochemical signs of opiate withdrawal

“…Withdrawal signs not affected by galnon treatment in galanin knockout mice were also not strongly expressed in Galϩ͞ϩ mice. GalϪ͞Ϫ mice have previously been shown to have alterations in neuropathic pain, survival of cholinergic neurons, and overall excitability (22,(26)(27)(28). Although a small, but significant, decrease in nociceptive threshold was seen in GalϪ͞Ϫ mice (Fig.…”

Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease

“…Compensatory and possibly neuroprotective actions of galanin are implied by reports that galanin pretreatment attenuates the physiological consequences of ischemia, concussion, and seizures (7,62,63). Also, in a recent description of mice that have a targeted deletion of the galanin gene, O'Meara and coworkers concluded that endogenous galanin plays an important role as a neuroprotective agent (64). Galanin overexpression in AD may reflect an attempt to compensate for neurodegeneration in AD, perhaps early in the development of the disease process.…”