Lost Voices, Missed Connections

Image from iStock/VLADGRIN. Humansare social animals.Westart our lives by forgingbonds and depend on them until death. Our social needs extendwell beyond survival or even comfort; we look to other people to endorse our values, define success, and validate intangible qualities such as tastes and what gives us pleasure. That we take these transactions and their joys and anguishes for granted underscores how ingrained they are. It isn’t surprising then thatconditionsaffectingour ability tobreathe thesocial air are considered most debilitating. Quintessentially, autism is a disorder of communication, characterized,amongothersymptoms,bydifficultywith social interaction. The rise in the numbers of diagnosed individuals in recent decades, alongwith advances in genetics and imaging techniques, is propelling a robust research response to decipher its biological underpinnings.One questionwith important therapeutic implications is how do social deficits arise during development and are they malleable in adulthood? With this in mind, Guoping Feng and colleagues have investigated the developmental contributions of a mutation in Shank3 to autism-like behaviors in mice (Mei et al., 2016). Feng finds that certain behavioral abnormalities found in mutant mice can be rescued by restoring Shank3 expression in the adult brain. Unexpectedly, among the behaviors disrupted by the mutation, social deficits turned out to be the ones with the largest degree of plasticity, suggesting that expression of thisgene inadulthoodmay impactsomedeep-seatedabilities. Such results are heartening, as they indicate that social deficits may be altered via molecular interventions. This conclusion is reinforced by the findings of Ivan Galimberti and colleagues, who also tackle the potential for therapeutic interventions in Shank3 mutant mice (Bidinosti et al., 2016). Their approach, informed by the analysis of the signaling pathways disrupted by the mutation, shows that pharmacological manipulation of the CLK2 kinase and the Akt pathway can specifically rescue social behaviors. Aside from providing insight into the molecular underpinnings of these phenotypes, this study points to potentially druggable targets, raising hopes for interventions that could help patients beyond childhood. Schizophrenia is another disorder where social deficits feature prominently. They are typically linked to impairments in social cognition: the ability to encode andprocess emotions and other memories associated with social situations. While schizophrenia is often equatedwith its more idiosyncratic features—hallucinations and delusions—the lack of social functioning is unsurprisingly a big impediment to functional recovery of patients. Social cognition was recently shown to be controlledby theCA2 regionof thehippocampus (Hitti andSiegelbaum, 2014; Stevenson and Caldwell, 2014), and analysis of socialmemory inamousemodel of the22q11deletion, agenetic lesion associated with schizophrenia, by Vivien Chevaleyre, Joseph Gogos, and colleagues shows that the CA2 area is anatomically and functionally altered in these mice and that these changesoccurduring a timeframe that parallels diseaseonset inhumans (Piskorowski et al., 2016).Changes to the CA2 have been noted in patients, and the functional dissection of its role in social memory nowmakes it an attractive area for future therapeutic interventions. Studies of mutant alleles have been spearheaded by the amenability of mice to genetic manipulations; however, mouse models cannot fully recapitulate human social behaviors. The recent creation of cynomolgus monkeys carrying a mutation in theMECP2 gene associated with Rett syndrome and displaying autistic-like phenotypes, including reduced social interaction and heightened stress responses (Liu et al., 2016), provides, however, a model which may in some aspects be more suitable for analysis of complex behaviors. Transgenic non-human primates have been previously applied to study neurodegenerative diseases (Yang et al., 2008) and may now allow us to pin down the more elusive facets of brain function and how they unravel in mental illness.