Faculty Bibliography

Background: GWAS studies in schizophrenia have not yielded targets for person-specific interventions. Alternatively, studies can focus on genes that were initially identified as harboring disruptive de novo mutations in sporadic cases. We examined the impact of four such genes on illness phenotypes. Methods: Structured interviews (DIGS), cognition (WAIS III), symptoms (PANSS) were examined in 48 genotyped cases finding that over 30% of the sample carried a rare/ missense mutations in any of 4 genes. Gene carrier groups were compared to cases without any of these mutations and healthy controls. Results: Carriers of disrupted genes showed significant differences, as follows: SLC39A13 (zinc transporter) (n=4) had the greatest psychopathology and severe cognitive deficits; TGM5 (n=4) had fewer symptoms but slower processing speed; PTPRG (n=5) had prematurity, childhood psychosis and good cognition except poor working memory; ARMS/KIDINS220 (n=5) had comparable severe pathology in all symptom factors and cognitive scores, though degeneration is suggested in light of their early accomplishments. Individual case vignettes highlighted familial psychosis, learning disorders, substance abuse, traumatic brain injuries and medical comorbidity in all 4 subgroups. Conclusions: The results suggest that genes prone to de novo mutations in sporadic cases may provide missing leverage to resolve the complexity of schizophrenia. A differential focus on working memory, processing speed, neuroprotection and zinc treatment should be pursued for these newly identified conditions. Other findings are that ethnicity may not limit genetic research when the focus is on gene function rather than particular sequence variations, and that premorbid exposures may sometimes reflect pleiotrophic effects of psychosis vulnerability genes rather than exposures producing nongenetic phenocopies. This novel approach may be applicable to other complex disorders

The correlation between sleep integrity and attentional performance is normally interpreted as poor sleep causing impaired attention. Here, we provide an alternative explanation for this correlation: common thalamic circuits regulate sensory processing across sleep and attention, and their disruption may lead to correlated dysfunction. Using multi-electrode recordings in mice, we find that rate and rhythmicity of thalamic reticular nucleus (TRN) neurons are predictive of their functional organization in sleep and suggestive of their participation in sensory processing across states. Surprisingly, TRN neurons associated with spindles in sleep are also associated with alpha oscillations during attention. As such, we propose that common thalamic circuit principles regulate sensory processing in a state-invariant manner and that in certain disorders, targeting these circuits may be a more viable therapeutic strategy than considering individual states in isolation.

Until now, most large-scale studies of humans have either focused on very specific domains of inquiry or have relied on between-subjects approaches. While these previous studies have been invaluable for revealing important biological factors in cardiac health or social factors in retirement choices, no single repository contains anything like a complete record of the health, education, genetics, environmental, and lifestyle profiles of a large group of individuals at the within-subject level. This seems critical today because emerging evidence about the dynamic interplay between biology, behavior, and the environment point to a pressing need for just the kind of large-scale, long-term synoptic dataset that does not yet exist at the within-subject level. At the same time that the need for such a dataset is becoming clear, there is also growing evidence that just such a synoptic dataset may now be obtainable-at least at moderate scale-using contemporary big data approaches. To this end, we introduce the Kavli HUMAN Project (KHP), an effort to aggregate data from 2,500 New York City households in all five boroughs (roughly 10,000 individuals) whose biology and behavior will be measured using an unprecedented array of modalities over 20 years. It will also richly measure environmental conditions and events that KHP members experience using a geographic information system database of unparalleled scale, currently under construction in New York. In this manner, KHP will offer both synoptic and granular views of how human health and behavior coevolve over the life cycle and why they evolve differently for different people. In turn, we argue that this will allow for new discovery-based scientific approaches, rooted in big data analytics, to improving the health and quality of human life, particularly in urban contexts.

ALS is a devastating disease, progressing from detachment of motor nerve terminals to paralytic, lethal respiratory failure within several years of diagnosis. The mechanisms responsible for axon withdrawal are poorly understood, but the loss of neuromuscular synapses is sufficient to cause muscle paralysis and therefore central to the disease. Although the subsequent loss of motor neurons has received more attention, preventing or delaying motor neuron cell death without preserving neuromuscular synapses cannot stop disease progression. Skeletal muscles provide retrograde signals that promote the differentiation and stabilization of motor nerve terminals (1, 2). The production of retrograde signals depends upon a synaptic receptor tyrosine kinase, termed MuSK, and Lrp4, a receptor for Agrin that forms a complex with MuSK (3). Because a failure to maintain neuromuscular synapses is central to all forms of ALS, we tested whether increasing retrograde signalling in SOD1^G93A transgenic mice would stabilize neuromuscular synapses, delay axon withdrawal and ameliorate disease symptoms (4). We found that a modest increase in MuSK expression is sufficient to maintain neuromuscular synapses in SOD1^G93A mice, delaying muscle denervation and improving muscle function for over one month (4). Thus, the loss of motor nerve terminals can be delayed by co-opting a retrograde signalling pathway that normally functions to stimulate the differentiation of these terminals (4). These findings suggest a novel therapeutic approach to slow the steady decline in motor function in ALS. Moreover, because motor axon withdrawal is an early, characteristic and critical feature of disease in all forms of ALS, increasing MuSK activity might provide benefit in both familial and sporadic forms of ALS. We sought a more practical therapeutic approach to activate MuSK in vivo. A previous study reported that two human single chain variable region antibodies (ScFv) to MuSK, as well as IgG molecules reconstituted from these ScFv antibodies, stimulate MuSK in cultured myotubes (5). Thus, these antibodies provide an attractive means to activate MuSK in vivo. We found that a single injection of a humanized agonist antibody to MuSK substantially reduced denervation and increased innervation for one month. Thus, increasing MuSK activity, after denervation and disease symptoms were evident, slows synaptic loss. We are currently studying whether the agonist antibody improves motor function and whether chronic dosing with a murinized agonist antibody preserves synapses, improves motor performance, reduces motor neuron cell death and prolongs longevity of SOD1^G93A mice

Olfactory information is synthesized within the olfactory cortex to provide not only an odor percept, but also a contextual significance that supports appropriate behavioral response to specific odor cues. The piriform cortex serves as a communication hub within this circuit by sharing reciprocal connectivity with higher processing regions, such as the lateral entorhinal cortex and amygdala. The functional significance of these descending inputs on piriform cortical processing of odorants is currently not well understood. We have employed optogenetic methods to selectively stimulate lateral and basolateral amygdala (BLA) afferent fibers innervating the posterior piriform cortex (pPCX) to quantify BLA modulation of pPCX odor-evoked activity. Single unit odor-evoked activity of anesthetized BLA-infected animals was significantly modulated compared with control animal recordings, with individual cells displaying either enhancement or suppression of odor-driven spiking. In addition, BLA activation induced a decorrelation of odor-evoked pPCX ensemble activity relative to odor alone. Together these results indicate a modulatory role in pPCX odor processing for the BLA complex. This interaction could contribute to learned changes in PCX activity following associative conditioning, as well as support alternate patterns of odor processing that are state-dependent.

Most drugs exert their beneficial and adverse effects through their combined action on several different molecular targets (polypharmacology). The true molecular fingerprint of the direct action of a drug has two components: the ensemble of all the receptors upon which a drug acts and their level of expression in organs/tissues. Conversely, the fingerprint of the adverse effects of a drug may derive from its action in bystander tissues. The ensemble of targets is almost always only partially known. Here we describe an approach improving upon and integrating both components: in silico identification of a more comprehensive ensemble of targets for any drug weighted by the expression of those receptors in relevant tissues. Our system combines more than 300,000 experimentally determined bioactivity values from the ChEMBL database and 4.2 billion molecular docking scores. We integrated these scores with gene expression data for human receptors across a panel of human tissues to produce drug-specific tissue-receptor (historeceptomics) scores. A statistical model was designed to identify significant scores, which define an improved fingerprint representing the unique activity of any drug. These multi-dimensional historeceptomic fingerprints describe, in a novel, intuitive, and easy to interpret style, the holistic, in vivo picture of the mechanism of any drug's action. Valuable applications in drug discovery and personalized medicine, including the identification of molecular signatures for drugs with polypharmacologic modes of action, detection of tissue-specific adverse effects of drugs, matching molecular signatures of a disease to drugs, target identification for bioactive compounds with unknown receptors, and hypothesis generation for drug/compound phenotypes may be enabled by this approach. The system has been deployed at drugable.org for access through a user-friendly web site.