A genetic interaction network containing approximately 1000 genes and approximately 4000 interactions was mapped by crossing mutations in 132 different query genes into a set of approximately 4700 viable gene yeast deletion mutants and scoring the double mutant progeny for fitness defects. Network connectivity was predictive of function because interactions often occurred among functionally related genes, and similar patterns of interactions tended to identify components of the same pathway. The genetic network exhibited dense local neighborhoods; therefore, the position of a gene on a partially mapped network is predictive of other genetic interactions. Because digenic interactions are common in yeast, similar networks may underlie the complex genetics associated with inherited phenotypes in other organisms.

The balance between excitatory and inhibitory synapses is a tightly regulated process that requires differential recruitment of proteins that dictate the specificity of newly formed contacts. However, factors that control this process remain unidentified. Here we show that members of the neuroligin (NLG) family, including NLG1, NLG2, and NLG3, drive the formation of both excitatory and inhibitory presynaptic contacts. The enrichment of endogenous NLG1 at excitatory contacts and NLG2 at inhibitory synapses supports an important in vivo role for these proteins in the development of both types of contacts. Immunocytochemical and electrophysiological analysis showed that the effects on excitatory and inhibitory synapses can be blocked by treatment with a fusion protein containing the extracellular domain of neurexin-1␤. We also found that overexpression of PSD-95, a postsynaptic binding partner of NLGs, resulted in a shift in the distribution of NLG2 from inhibitory to excitatory synapses. These findings reveal a critical role for NLGs and their synaptic partners in controlling the number of inhibitory and excitatory synapses. Furthermore, relative levels of PSD-95 alter the ratio of excitatory to inhibitory synaptic contacts by sequestering members of the NLG family to excitatory synapses.Synapse formation is a tightly regulated process that involves the recruitment of specific cell adhesion molecules and scaffolding proteins to newly formed contacts between an axon and a dendrite (1-3). In the brain, excitatory and inhibitory synaptic transmission is mainly mediated by two neurotransmitters: glutamate, which is released at excitatory glutamatergic synaptic contacts, and GABA, 1 which is released at inhibitory GABAergic synapses. Initial transformation of a contact to either an excitatory or inhibitory synapse is thought to be controlled by spatial and temporal changes in protein content. This process is critical because an appropriate balance between excitatory and inhibitory synapses is required for proper neuronal excitability and function (2, 4 -6). However, molecular events that control differentiation of a contact into either an excitatory or inhibitory synapse remain unknown.The postsynaptic density protein, PSD-95, is a molecule that is exclusively localized to glutamatergic synapses and regulates clustering of AMPA receptors through association with stargazin (7, 8). Through its third PDZ (PSD-95/Dlg/ZO-1) homology domain, PSD-95 also recruits neuroligin-1 (NLG1), a cell adhesion molecule involved in synapse formation (9 -11). These findings indicate that association of PSD-95 with NLG1 is involved in excitatory synapse development. Recent work by Prange et al. (12) showed that NLG1 can drive both excitatory and inhibitory presynaptic contact formation. These results suggested that NLGs are involved in inhibitory synapse formation. Our work also showed that the effects of NLG1 on postsynaptic differentiation were less dramatic. Overexpression of NLG1 modestly increased the total number of excitatory posts...

Processing of neural information is thought to occur by integration of excitatory and inhibitory synaptic inputs. As such, precise control mechanisms must exist to maintain an appropriate balance between each synapse type. Recent findings indicate that neuroligins and their synaptic binding partners modulate the development of both excitatory and inhibitory synapses. Here we highlight these findings and discuss a mechanism potentially involved in controlling the balance between excitation and inhibition.