Neuroligins (NLs) are a family of neural cell-adhesion molecules that are involved in excitatory/inhibitory synapse specification. Multiple members of the NL family (including NL1) and their binding partners have been linked to cases of human autism and mental retardation. We have now characterized NL1-deficient mice in autism-and mental retardation-relevant behavioral tasks. NL1 knock-out (KO) mice display deficits in spatial learning and memory that correlate with impaired hippocampal long-term potentiation. In addition, NL1 KO mice exhibit a dramatic increase in repetitive, stereotyped grooming behavior, a potential autism-relevant abnormality. This repetitive grooming abnormality in NL1 KO mice is associated with a reduced NMDA/AMPA ratio at corticostriatal synapses. Interestingly, we further demonstrate that the increased repetitive grooming phenotype can be rescued in adult mice by administration of the NMDA receptor partial coagonist D-cycloserine. Broadly, these data are consistent with a role of synaptic cell-adhesion molecules in general, and NL1 in particular, in autism and implicate reduced excitatory synaptic transmission as a potential mechanism and treatment target for repetitive behavioral abnormalities.

Fertilization is a matter of life or death. In animals of sexual reproduction, the appropriate communication between mature and competent male and female gametes determines the generation of a new individual. Ion channels are key elements in the dialogue between sperm, its environment, and the egg. Components from the outer layer of the egg induce ion permeability changes in sperm that regulate sperm motility, chemotaxis, and the acrosome reaction. Sperm are tiny differentiated terminal cells unable to synthesize protein and difficult to study electrophysiologically. Thus understanding how sperm ion channels participate in fertilization requires combining planar bilayer techniques, in vivo measurements of membrane potential, intracellular Ca2+ and intracellular pH using fluorescent probes, patch-clamp recordings, and molecular cloning and heterologous expression. Spermatogenic cells are larger than sperm and synthesize the ion channels that will end up in mature sperm. Correlating the presence and cellular distribution of various ion channels with their functional status at different stages of spermatogenesis is contributing to understand their participation in differentiation and in sperm physiology. The multi-faceted approach being used to unravel sperm ion channel function and regulation is yielding valuable information about the finely orchestrated events that lead to sperm activation, induction of the acrosome reaction, and in the end to the miracle of life.

Mammalian sperm are incapable of fertilizing eggs immediately after ejaculation; they acquire fertilization capacity after residing in the female tract for a finite period of time. The physiological changes sperm undergo in the female reproductive tract that render sperm able to fertilize constitute the phenomenon of "sperm capacitation." We have demonstrated that capacitation is associated with an increase in the tyrosine phosphorylation of a subset of proteins and that these events are regulated by an HCO 3 ؊ /cAMP-dependent pathway involving protein kinase A. Capacitation is also accompanied by hyperpolarization of the sperm plasma membrane. Here we present evidence that, in addition to its role in the regulation of adenylyl cyclase, HCO 3 ؊ has a role in the regulation of plasma membrane potential in mouse sperm. Addition of HCO 3 ؊ but not Cl ؊ induces a hyperpolarizing current in mouse sperm plasma membranes. This HCO 3 ؊ -dependent hyperpolarization was not observed when Na ؉ was replaced by the nonpermeant cation choline ؉ . Replacement of Na ؉ by choline ؉ also inhibited the capacitation-associated increase in protein tyrosine phosphorylation as well as the zona pellucida-induced acrosome reaction. The lack of an increase in protein tyrosine phosphorylation was overcome by the presence of cAMP agonists in the incubation medium. The lack of a hyperpolarizing HCO 3 ؊ current and the inhibition of the capacitation-dependent increase in protein tyrosine phosphorylation in the absence of Na ؉ suggest that a Na ؉ /HCO 3 ؊ cotransporter is present in mouse sperm and is coupled to events regulating capacitation.Upon ejaculation, mammalian sperm are not able to fertilize; they become fertilization-competent during transit through the female reproductive tract (1). The molecular, biochemical, and physiological changes that occur in sperm while in the female tract are collectively referred to as capacitation. During capacitation, changes in membrane dynamics and properties, enzyme activities, and motility render spermatozoa responsive to stimuli that induce the acrosome reaction and prepare these cells for penetration of the egg vestments prior to fertilization. Mammalian sperm capacitation is also accompanied by the hyperpolarization of the sperm plasma membrane (3). Hyperpolarization is observed as an increase in the intracellular negative charges when compared with the extracellular environment. Although it is not clear how sperm plasma membrane potential is regulated during capacitation, it appears that membrane hyperpolarization may be partially because of an enhanced K ϩ permeability as a result of a decrease in inhibitory modulation of K ϩ channels (3). Recently, Muñ oz-Garay et al. (4) demonstrated with patch clamp techniques that inward rectifying K ϩ channels are expressed in mouse spermatogenic cells and proposed that these channels may be responsible for the capacitation-associated membrane hyperpolarization. Interestingly, Ba 2ϩ blocks these K ϩ channels with an IC 50 similar to that shown to inhibit ...