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...

Previous studies have shown that pharmacological activation of presynaptic kainate receptors at glutamatergic synapses facilitates or depresses transmission in a dose-dependent manner. However, the only synaptically activated kainate autoreceptor described to date is facilitatory. Here, we describe a kainate autoreceptor that depresses synaptic transmission. This autoreceptor is present at developing thalamocortical synapses in the barrel cortex, specifically regulates transmission at frequencies corresponding to those observed in vivo during whisker activation, and is developmentally down regulated during the first postnatal week. This receptor may, therefore, limit the transfer of high-frequency activity to the developing cortex, the loss of which mechanism may be important for the maturation of sensory processing.

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