Neuroligins are cell adhesion molecules that interact with neurexins on adjacent cells to promote glutamatergic and GABAergic synapse formation in culture. We show here that neuroligin enhances nicotinic synapses on neurons in culture, increasing synaptic input. When neuroligin is overexpressed in neurons, the extracellular domain induces presynaptic specializations in adjacent cholinergic neurons as visualized by SV2 puncta. The intracellular domain is required to translate the SV2 puncta into synaptic input as reflected by increases in the frequency of spontaneous mini-synaptic currents. The PDZ-binding motif of neuroligin is not needed for these effects. Together, the extracellular and proximal intracellular domains of neuroligin are sufficient to induce presynaptic specializations, align them over postsynaptic receptor clusters, and increase synaptic function. Manipulation of endogenous neuroligin with beta-neurexin-expressing cells confirms its presence; repressing function with dominant negative constructs and inhibitory shRNA shows that endogenous neuroligin helps confer functionality on existing nicotinic synaptic contacts. Endogenous neuroligin does not appear to be required, however, for initial formation of the contacts, suggesting that other components under these conditions can also initiate synapse formation. The results indicate that postsynaptic neuroligin is important for functional nicotinic synapses on neurons and that the effects achieved will likely depend on neuroligin levels.

The cytokine IL-18 acts on the CNS both in physiological and pathological conditions. Its action occurs through the heterodimeric receptor IL-18Rα\β. To better understand IL-18 central effects, we investigated in the mouse brain the distribution of two IL-18Rα transcripts, a full length and an isoform lacking the intracellular domain hypothesized to be a decoy receptor. Both isoforms were expressed in neurons throughout the brain primarily with overlapping distribution but also with some unique pattern. These data suggest that IL-18 may modulate neuronal functions and that its action may be regulated through expression of a decoy receptor.

Neuropeptide galanin modulates a variety of central nervous system functions by signaling through three G-protein-coupled receptor subtypes, GalR1 through GalR3. Galanin and its receptors are expressed at high levels in the limbic structures of the rodent brain. Intracerebroventricular injection of galanin has been shown to modulate depression and anxiety-like behaviors in the rat. We have previously shown that chronic antidepressant treatments increase the binding of a GalR2-preferring ligand, galanin (2-11), to the dorsal raphe nucleus (DRN) of the rat, which, along with the finding that intra-DRN infusion of galanin (2-11) increases the release of serotonin in the hippocampus, suggests that GalR2 signaling might exert antidepressant-like actions by modulating ascending serotonergic outflow. Recently, two research groups reported their phenotypic analysis of a GalR2 knockout (GalR2KO) mouse line, produced by gene-trapping method and maintained on a 129S1/SvImJ genetic background. The only positive finding in that GalR2KO mouse line was an anxiogenic-like phenotype specific to the elevated plus-maze. Because it is known that genetic background can affect the outcome of behavioral tests, in the present study, we analyzed a separate GalR2KO line, which was produced by targeted deletion and maintained on a C57BL/6 background, using a different set of depression- and anxiety-related tests. GalR2KO mice exhibited a more persistent depressive-like phenotype in the learned helplessness paradigm as well as increased immobility in the tail suspension test when results from the present studies were combined by fixed effect meta-analysis with that reported by Gottsch and colleagues. GalR2KO mutants showed anxiety-like behavior comparable to wild-type littermates in the elevated plus-maze, open-field, and light-dark transfer tests. The present findings are consistent with a predicted antidepressant-like effect of GalR2 signaling, suggesting that GalR2 might be a valid drug target for depressive disorders.

We have characterized a newly generated mouse model of obesity, a mouse strain deficient in all five previously described leptin receptor isoforms. These transgenic mice, named the db 333 /db 333 mice, were identified from an ENU mutagenesis screen and carry a point mutation in the seventh exon of the db gene encoding the leptin receptor, resulting in a premature stop codon (Y 333 Stop) and gene product that lacks STAT signaling domains. db 333 /db 333 mice have a morbidly obese phenotype, with body weights diverging from wild-type as early as 4 weeks of age (P<0.05). To determine the contribution of the short isoforms of the leptin receptor in this metabolic phenotype we performed an extensive metabolic characterization of the db 333 /db 333 mouse in relation to the well characterized db/db mouse lacking only the long form of the leptin receptor. db 333 /db 333 mice have similar endocrine and metabolic parameters as previously described in other leptin receptor transgenic mice including db/db mice that lack only the long isoform of the leptin receptor. However, db 333 /db 333 mice show a subtle trend towards higher body weight, insulin levels, lower oxygen production, carbon dioxide production, respiratory efficiency ratio and temperature than db/db mice suggesting the short isoforms may play an additional role in energy homeostasis.