Secreted and membrane-tethered mammalian neuromodulators from the Ly6/uPAR family are involved in regulation of many physiological processes. Some of them are expressed in the CNS in the neurons of different brain regions and target neuronal membrane receptors. Thus, Lynx1 potentiates nicotinic acetylcholine receptors (nAChRs) in the brain, while others like Lypd6 and Lypd6b suppress it. However, the mechanisms underlying the regulation of cognitive processes by these neuromodulators remain unclear. Here, we showed that water-soluble analogue of Lynx1 (ws-Lynx-1) targets α7-nAChRs both in the hippocampal neurons and astrocytes. Incubation of astrocytes with ws-Lynx1 increased expression of connexins 30 and 43; α4, α5, and β4 integrins; and E- and P-cadherins. Ws-Lynx1 reduced secretion of pro-inflammatory adhesion factors ICAM-1, PSGL-1, and VCAM-1 and downregulated secretion of CD44 and NCAM, which inhibit synaptic plasticity. Moreover, increased astrocytic secretion of the dendritic growth activator ALCAM and neurogenesis regulator E-selectin was observed. Incubation of neurons with ws-Lynx1 potentiated α7-nAChRs and upregulated dendritic spine density. Thus, the pro-cognitive activity of ws-Lynx1 observed previously can be explained by stimulation of astrocytic network and signaling together with up-regulation of spinogenesis, potentiation of the α7-nAChRs, and neuronal and synaptic plasticity. For comparison, influence of water-soluble analogues of a set of Ly6/uPAR proteins (SLURP-1, SLURP-2, Lypd6, Lypd6b, and PSCA) on dendritic spine density and diameter was studied. Data obtained give new insights on the role of Ly6/uPAR proteins in the brain and open new prospects for the development of drugs to improve cognitive function.