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Engagement of integrins by the extracellular matrix initiates signaling cascades that drive a variety of cellular functions, including neuronal migration and axonal pathfinding in the brain. Multiple lines of evidence link the ITGB3 gene encoding the integrin β3 subunit with the serotonin (5-HT) system, likely via its modulation of the 5-HT transporter (SERT). The ITGB3 coding polymorphism Leu33Pro (rs5918, Pl(A2)) produces hyperactive αvβ3 receptors that influence whole blood 5-HT levels and may influence risk for autism spectrum disorder (ASD). Using a phenome-wide scan of psychiatric diagnoses, we found significant, male-specific associations between the Pro33 allele and attention-deficit hyperactivity disorder and ASDs. Here, we utilized knock-in (KI) mice expressing an Itgb3 variant that phenocopies the human Pro33 variant to elucidate the consequences of constitutively enhanced αvβ3 signaling to the 5-HT system in the brain. KI mice displayed deficits in multiple behaviors, including anxiety, repetitive, and social behaviors. Anatomical studies revealed a significant decrease in 5-HT synapses in the midbrain, accompanied by decreases in SERT activity and reduced localization of SERTs to integrin adhesion complexes in KI synapses. Inhibition of focal adhesion kinase (FAK) rescued SERT function in KI synapses, demonstrating that constitutive active FAK signaling downstream of the Pro32Pro33 integrin αvβ3 suppresses SERT activity. Our studies identify a complex regulation of 5-HT homeostasis and behaviors by integrin αvβ3, revealing an important role for integrins in modulating risk for neuropsychiatric disorders.SIGNIFICANCE STATEMENTThe integrin β3 Leu33Pro coding polymorphism has been associated with ASD within a subgroup of patients with elevated blood 5-HT levels, linking integrin β3, 5-HT and ASD risk. We capitalized on these interactions to demonstrate that the Pro33 coding variation in the murine integrin β3 recapitulates the sex-dependent neurochemical and behavioral attributes of ASD. Using state-of-the-art techniques, we show that presynaptic 5-HT function is altered in these mice, and that the localization of 5-HT transporters to specific compartments within the synapse, disrupted by the integrin β3 Pro33 mutation, is critical for appropriate reuptake of 5-HT. Our studies provide fundamental insight into the genetic network regulating 5-HT neurotransmission in the central nervous system that is also associated with ASD risk.
Copyright © 2017 the authors.
Voltage-gated Cav1.2 and Cav1.3 (L-type) Ca(2+) channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca(2+)-dependent facilitation of voltage-gated Cav1.3 Ca(2+) channels in transfected cells. Mice lacking densin (densin KO) exhibit defects in synaptic plasticity, spatial memory, and increased anxiety-related behaviors --phenotypes that more closely match those in mice lacking Cav1.2 than Cav1.3. Thus, we investigated the functional impact of densin on Cav1.2. We report that densin is an essential regulator of Cav1.2 in neurons, but has distinct modulatory effects compared to its regulation of Cav1.3. Densin binds to the N-terminal domain of Cav1.2 but not Cav1.3, and increases Cav1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Cav1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Cav1.2 channels, overexpression of densin increases the clustering of Cav1.2 in dendrites of hippocampal neurons in culture. Compared to wild-type mice, the cell-surface levels of Cav1.2 in the brain as well as Cav1.2 current density and signaling to the nucleus are reduced in neurons from densin KO mice. We conclude that densin is an essential regulator of neuronal Cav1 channels and ensures efficient Cav1.2 Ca(2+) signaling at excitatory synapses.SIGNIFICANCE STATEMENTThe number and localization of voltage-gated Cav Ca(2+) channels are crucial determinants of neuronal excitability and synaptic transmission. We report that a protein that is highly enriched at excitatory synapses in the brain, densin-180, enhances the cell-surface trafficking and postsynaptic localization of Cav1.2 L-type Ca(2+) channels in neurons. This interaction promotes coupling of Cav1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Cav1.2 in regulating cognition and mood.
Copyright © 2017 the authors.
Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a de novo Glu183 to Val (E183V) mutation in the CaMKIIα catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIα substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIα-WT autophosphorylation. The E183V mutation also reduces CaMKIIα binding to established ASD-linked proteins, such as Shank3 and subunits of L-type calcium channels and NMDA receptors, and increases CaMKIIα turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIα targeting to dendritic spines. Moreover, neuronal expression of CaMKIIα-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIα-E183V mutation have lower total forebrain CaMKIIα levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIα-E183V mice also display aberrant behavioral phenotypes including hyperactivity, social interaction deficits and increased repetitive behaviors. Taken together, these data suggest that CaMKIIα plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes.
SIGNIFICANCE STATEMENT - Many ASD-linked mutations disrupt the function of synaptic proteins, but no single gene accounts for >1% of total ASD cases. The molecular networks and mechanisms that couple the primary deficits caused by these individual mutations to core behavioral symptoms of ASD remain poorly understood. Here, we provide the first characterization of a mutation in the gene encoding CaMKIIα linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked de novo CAMK2A mutation disrupts multiple CaMKII functions, induces synaptic deficits and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD.
Copyright © 2017 the authors.
UNLABELLED - The evolved capacity for third-party punishment is considered crucial to the emergence and maintenance of elaborate human social organization and is central to the modern provision of fairness and justice within society. Although it is well established that the mental state of the offender and the severity of the harm he caused are the two primary predictors of punishment decisions, the precise cognitive and brain mechanisms by which these distinct components are evaluated and integrated into a punishment decision are poorly understood. Using fMRI, here we implement a novel experimental design to functionally dissociate the mechanisms underlying evaluation, integration, and decision that were conflated in previous studies of third-party punishment. Behaviorally, the punishment decision is primarily defined by a superadditive interaction between harm and mental state, with subjects weighing the interaction factor more than the single factors of harm and mental state. On a neural level, evaluation of harms engaged brain areas associated with affective and somatosensory processing, whereas mental state evaluation primarily recruited circuitry involved in mentalization. Harm and mental state evaluations are integrated in medial prefrontal and posterior cingulate structures, with the amygdala acting as a pivotal hub of the interaction between harm and mental state. This integrated information is used by the right dorsolateral prefrontal cortex at the time of the decision to assign an appropriate punishment through a distributed coding system. Together, these findings provide a blueprint of the brain mechanisms by which neutral third parties render punishment decisions.
SIGNIFICANCE STATEMENT - Punishment undergirds large-scale cooperation and helps dispense criminal justice. Yet it is currently unknown precisely how people assess the mental states of offenders, evaluate the harms they caused, and integrate those two components into a single punishment decision. Using a new design, we isolated these three processes, identifying the distinct brain systems and activities that enable each. Additional findings suggest that the amygdala plays a crucial role in mediating the interaction of mental state and harm information, whereas the dorsolateral prefrontal cortex plays a crucial, final-stage role, both in integrating mental state and harm information and in selecting a suitable punishment amount. These findings deepen our understanding of how punishment decisions are made, which may someday help to improve them.
Copyright © 2016 Ginther et al.
Oxytocin is a neuropeptide important for social behaviors such as maternal care and parent-infant bonding. It is believed that oxytocin receptor signaling in the brain is critical for these behaviors, but it is unknown precisely when and where oxytocin receptors are expressed or which neural circuits are directly sensitive to oxytocin. To overcome this challenge, we generated specific antibodies to the mouse oxytocin receptor and examined receptor expression throughout the brain. We identified a distributed network of female mouse brain regions for maternal behaviors that are especially enriched for oxytocin receptors, including the piriform cortex, the left auditory cortex, and CA2 of the hippocampus. Electron microscopic analysis of the cerebral cortex revealed that oxytocin receptors were mainly expressed at synapses, as well as on axons and glial processes. Functionally, oxytocin transiently reduced synaptic inhibition in multiple brain regions and enabled long-term synaptic plasticity in the auditory cortex. Thus modulation of inhibition may be a general mechanism by which oxytocin can act throughout the brain to regulate parental behaviors and social cognition.
Copyright © 2016 the authors 0270-6474/16/362517-19$15.00/0.
Aversive olfactory classical conditioning has been the standard method to assess Drosophila learning and memory behavior for decades, yet training and testing are conducted manually under exceedingly labor-intensive conditions. To overcome this severe limitation, a fully automated, inexpensive system has been developed, which allows accurate and efficient Pavlovian associative learning/memory analyses for high-throughput pharmacological and genetic studies.
In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome.
Selenium (Se) is essential for both brain development and male fertility. Male mice lacking two key genes involved in Se metabolism (Scly(-/-)Sepp1(-/-) mice), selenoprotein P (Sepp1) and Sec lyase (Scly), develop severe neurological dysfunction, neurodegeneration, and audiogenic seizures that manifest beginning in early adulthood. We demonstrate that prepubescent castration of Scly(-/-)Sepp1(-/-) mice prevents behavioral deficits, attenuates neurodegeneration, rescues maturation of GABAergic inhibition, and increases brain selenoprotein levels. Moreover, castration also yields similar neuroprotective benefits to Sepp1(-/-) and wild-type mice challenged with Se-deficient diets. Our data show that, under Se-compromised conditions, the brain and testes compete for Se utilization, with concomitant effects on neurodevelopment and neurodegeneration.
Mesoscale local functional organizations of the primate spinal cord are largely unknown. Using high-resolution fMRI at 9.4 T, we identified distinct interhorn and intersegment fMRI activation patterns to tactile versus nociceptive heat stimulation of digits in lightly anesthetized monkeys. Within a spinal segment, 8 Hz vibrotactile stimuli elicited predominantly fMRI activations in the middle part of ipsilateral dorsal horn (iDH), along with significantly weaker activations in ipsilateral (iVH) and contralateral (cVH) ventral horns. In contrast, nociceptive heat stimuli evoked widespread strong activations in the superficial part of iDH, as well as in iVH and contralateral dorsal (cDH) horns. As controls, only weak signal fluctuations were detected in the white matter. The iDH responded most strongly to both tactile and heat stimuli, whereas the cVH and cDH responded selectively to tactile versus nociceptive heat, respectively. Across spinal segments, iDH activations were detected in three consecutive segments in both tactile and heat conditions. Heat responses, however, were more extensive along the cord, with strong activations in iVH and cDH in two consecutive segments. Subsequent subunit B of cholera toxin tracer histology confirmed that the spinal segments showing fMRI activations indeed received afferent inputs from the stimulated digits. Comparisons of the fMRI signal time courses in early somatosensory area 3b and iDH revealed very similar hemodynamic stimulus-response functions. In summary, we identified with fMRI distinct segmental networks for the processing of tactile and nociceptive heat stimuli in the cervical spinal cord of nonhuman primates. Significance statement: This is the first fMRI demonstration of distinct intrasegmental and intersegmental nociceptive heat and touch processing circuits in the spinal cord of nonhuman primates. This study provides novel insights into the local functional organizations of the primate spinal cord for pain and touch, information that will be valuable for designing and optimizing therapeutic interventions for chronic pain management.
Disruptions in corollary discharge (CD), motor signals that send information to sensory areas and allow for prediction of sensory states, are argued to underlie the perceived loss of agency in schizophrenia. Behavioral and neurophysiological evidence for CD in primates comes largely from the saccadic double-step task, which requires participants to make two visually triggered saccadic eye movements in brief succession. Healthy individuals use CD to anticipate the change in eye position resulting from the first saccade when preparing the second saccade. In the current study with human participants, schizophrenia patients and healthy controls of both sexes performed a modified double-step task. Most trials required a saccade to a single visual target (T1). On a subset of trials, a second target (T2) was flashed shortly following T1. Subjects were instructed to look directly at T2. Healthy individuals also use CD to make rapid, corrective responses following erroneous saccades to T1. To assess CD in schizophrenia, we examined the following on error trials: (1) frequency and latency of corrective saccades, and (2) mislocalization of the corrective (second) saccade in the direction predicted by a failure to use CD to account for the first eye movement. Consistent with disrupted CD, patients made fewer and slower error corrections. Importantly, the corrective saccade vector angle was biased in a manner consistent with disrupted CD. These results provide novel and clear evidence for dysfunctional CD in the oculomotor system in patients with schizophrenia. Based on neurophysiology work, these disturbances might have their basis in medial thalamus dysfunction.