Faculty Bibliography

Lithium (Li+) is a drug widely employed for treating bipolar disorder, however the mechanism of action is not known. Here we study the effects of Li+ in cultured hippocampal neurons on a synaptic complex consisting of delta-catenin, a protein associated with cadherins whose mutation is linked to autism, and GRIP, an AMPA receptor (AMPAR) scaffolding protein, and the AMPAR subunit, GluA2. We show that Li+ elevates the level of delta-catenin in cultured neurons. delta-catenin binds to the ABP and GRIP proteins, which are synaptic scaffolds for GluA2. We show that Li+ increases the levels of GRIP and GluA2, consistent with Li+-induced elevation of delta-catenin. Using GluA2 mutants, we show that the increase in surface level of GluA2 requires GluA2 interaction with GRIP. The amplitude but not the frequency of mEPSCs was also increased by Li+ in cultured hippocampal neurons, confirming a functional effect and consistent with AMPAR stabilization at synapses. Furthermore, animals fed with Li+ show elevated synaptic levels of delta-catenin, GRIP, and GluA2 in the hippocampus, also consistent with the findings in cultured neurons. This work supports a model in which Li+ stabilizes delta-catenin, thus elevating a complex consisting of delta-catenin, GRIP and AMPARs in synapses of hippocampal neurons. Thus, the work suggests a mechanism by which Li+ can alter brain synaptic function that may be relevant to its pharmacologic action in treatment of neurological disease.

Execution of motor behaviors relies on the ability of circuits within the nervous system to engage functionally relevant subtypes of spinal motor neurons. While much attention has been given to the role of networks of spinal interneurons on setting the rhythm and pattern of output from locomotor circuits, recent studies suggest that motor neurons themselves can exert an instructive role in shaping the wiring and functional properties of locomotor networks. Alteration in the distribution of motor neuron subtypes also appears to have contributed to evolutionary transitions in the locomotor strategies used by land vertebrates. This review describes emerging evidence that motor neuron-derived cues can have a profound influence on the organization, wiring, and evolutionary diversification of locomotor circuits.

A fundamental question in developmental neuroscience is how hundreds of diverse cell types are generated to form specialized brain regions. The ganglionic eminences (GEs) are embryonic brain structures located in the ventral telencephalon that produce many inhibitory GABA (gamma-Aminobutyric acid)-ergic cell types, including long-range projection neurons and local interneurons (INs), which disperse widely throughout the brain. While much has been discovered about the origin and wiring of these cells, a major question remains: how do neurons originating in the GEs become specified during development as one differentiated subtype versus another? This review will cover recent work that has advanced our knowledge of the mechanisms governing cortical interneuron subtype specification, particularly progenitors' spatial origin, birthdates, lineage, and mode of division.

Social support can attenuate the behavioral and stress hormone response to threat, a phenomenon called social buffering. The mother's social buffering of the infant is one of the more robust examples, yet we understand little about the neurobiology. Using a rodent model, we explore the neurobiology of social buffering by assessing neural processing of the maternal odor, a major cue controlling social buffering in rat pups. We used pups before (Postnatal day (PN) 7) and after (PN14, PN23) the functional emergence of social buffering. Pups were injected with 14C 2-DG and presented with the maternal odor, a control preferred odor incapable of social buffering (acetophenone), or no odor. Brains were removed, processed for autoradiography and brain areas identified as important in adult social buffering were assessed, including the amygdala basolateral complex (BLA), medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). Results suggest dramatic changes in the processing of maternal odor. PN7 pups show mPFC and ACC activation, although PN14 pups showed no activation of the mPFC, ACC or BLA. All brain areas assessed were recruited by PN23. Additional analysis suggests substantial changes in functional connectivity across development. Together, these results imply complex nonlinear transitions in the neurobiology of social buffering in early life that may provide insight into the changing role of the mother in supporting social buffering.

Stromal cell-derived factor-1 (SDF-1) is a cytokine that is important in stem and progenitor cell recruitment in tissue repair after injury. Regenerative procedures using collagen membranes (CMs) are presently well established in periodontal and implant dentistry. The objective of this study is to test the subsequent effects of the released SDF-1 from a CM on bone regeneration compared to platelet-derived growth factor (PDGF) in vitro and in vivo. For in vitro studies, cell proliferation, alkaline phosphatase activity, and osteoblastic differentiation marker genes were assessed after MC3T3-E1 mouse preosteoblasts were cultured with CMs containing factors. In vivo effects were investigated by placement of CMs containing SDF-1 or PDGF using a rat mandibular bone defect model. At 4 weeks after the surgery, the new bone formation was measured using micro-computed tomography (microCT) and histological analysis. The results of in vitro studies revealed that CM delivery of SDF-1 significantly induced cell proliferation, ALP activity, and gene expression of all osteogenic markers compared to the CM alone or control, similar to PDGF. Quantitative and qualitative microCT analysis for volume of new bone formation and the percentage of new bone area showed that SDF-1-treated groups significantly increased and accelerated bone regeneration compared to control and CM alone. The enhancement of bone formation in SDF-1-treated animals was dose-dependent and with levels similar to those measured with PDGF. These results suggest that a CM with SDF-1 may be a great candidate for growth factor delivery that could be a substitute for PDGF in clinical procedures where bone regeneration is necessary.

OBJECTIVE: Adrenergic crises are a cardinal feature of familial dysautonomia (FD). Traditionally, adrenergic crises have been treated with the sympatholytic agent clonidine or with benzodiazepines, which can cause excessive sedation and respiratory depression. Dexmedetomidine is a centrally-acting alpha 2-adrenergic agonist with greater selectivity and shorter half-life than clonidine. We evaluated the preliminary effectiveness and safety of intravenous dexmedetomidine in the treatment of refractory adrenergic crisis in patients with FD. METHODS: Retrospective chart review of patients with genetically confirmed FD who received intravenous dexmedetomidine for refractory adrenergic crises. The primary outcome was preliminary effectiveness of dexmedetomidine defined as change in blood pressure (BP) and heart rate (HR) 1 h after the initiation of dexmedetomidine. Secondary outcomes included incidence of adverse events related to dexmedetomidine, hospital and intensive care unit (ICU) length of stay, and hemodynamic parameters 12 h after dexmedetomidine cessation. RESULTS: Nine patients over 14 admissions were included in the final analysis. At 1 h after the initiation of dexmedetomidine, systolic BP decreased from 160 +/- 7 to 122 +/- 7 mmHg (p = 0.0005), diastolic BP decreased from 103 +/- 6 to 65 +/- 8 (p = 0.0003), and HR decreased from 112 +/- 4 to 100 +/- 5 bpm (p = 0.0047). The median total adverse events during dexmedetomidine infusion was 1 per admission. Median hospital length of stay was 9 days [interquartile range (IQR) 3-11 days] and median ICU length of stay was 7 days (IQR 3-11 days). CONCLUSIONS: Intravenous dexmedetomidine is safe in patients with FD and appears to be effective to treat refractory adrenergic crisis. Dexmedetomidine may be considered in FD patients who do not respond to conventional clonidine and benzodiazepine pharmacotherapy.

While localizing sensory and motor deficits is one of the cornerstones of clinical neurology, behavioral and cognitive deficits in psychiatry remain impervious to this approach. In psychiatry, major challenges include the relative subtlety by which neural circuits are perturbed, and the limited understanding of how basic circuit functions relate to thought and behavior. Neurodevelopmental disorders offer a window to addressing the first challenge given their strong genetic underpinnings, which can be linked to biological mechanisms. Such links have benefited from genetic modeling in the mouse, and in this review we highlight how this small mammal is now allowing us to crack neural circuits as well. We review recent studies of mouse thalamus, discussing how they revealed general principles that may underlie human perception and attention. Controlling the magnitude (gain) of thalamic sensory responses is a mechanism of attention, and the mouse has enabled its functional dissection at an unprecedented resolution. Further, modeling human genetic neurodevelopmental disease in the mouse has shown how diminished thalamic gain control can lead to attention deficits. This breaks new ground in how we untangle the complexity of psychiatric diseases; by making thalamic circuits accessible to mechanistic dissection; the mouse has not only taught us how they fundamentally work, but also how their dysfunction can be precisely mapped onto behavioral and cognitive deficits. Future studies promise even more progress, with the hope that principled targeting of identified thalamic circuits can be uniquely therapeutic.Molecular Psychiatry advance online publication, 11 October 2016; doi:10.1038/mp.2016.183.