Valter Tucci

Sound-Driven Synaptic Inhibition in Primary Visual Cortex

Summary Multimodal objects and events activate many sensory cortical areas simultaneously. This is possibly reflected in reciprocal modulations of neuronal activity, even at the level of primary cortical areas. However, the synaptic character of these interareal interactions, and their impact on synaptic and behavioral sensory responses are unclear. Here, we found that activation of auditory cortex by a noise burst drove local GABAergic inhibition on supragranular pyramids of the mouse primary visual cortex, via cortico-cortical connections. This inhibition was generated by sound-driven excitation of a limited number of cells in infragranular visual cortical neurons. Consequently, visually driven synaptic and spike responses were reduced upon bimodal stimulation. Also, acoustic stimulation suppressed conditioned behavioral responses to a dim flash, an effect that was prevented by acute blockade of GABAergic transmission in visual cortex. Thus, auditory cortex activation by salient stimuli degrades potentially distracting sensory processing in visual cortex by recruiting local, translaminar, inhibitory circuits.

Reliability, robustness, and reproducibility in mouse behavioral phenotyping: a cross-laboratory study.

Establishing standard operating procedures (SOPs) as tools for the analysis of behavioral phenotypes is fundamental to mouse functional genomics. It is essential that the tests designed provide reliable measures of the process under investigation but most importantly that these are reproducible across both time and laboratories. For this reason, we devised and tested a set of SOPs to investigate mouse behavior. Five research centers were involved across France, Germany, Italy, and the UK in this study, as part of the EUMORPHIA program. All the procedures underwent a cross-validation experimental study to investigate the robustness of the designed protocols. Four inbred reference strains (C57BL/6J, C3HeB/FeJ, BALB/cByJ, 129S2/SvPas), reflecting their use as common background strains in mutagenesis programs, were analyzed to validate these tests. We demonstrate that the operating procedures employed, which includes open field, SHIRPA, grip-strength, rotarod, Y-maze, prepulse inhibition of acoustic startle response, and tail flick tests, generated reproducible results between laboratories for a number of the test output parameters. However, we also identified several uncontrolled variables that constitute confounding factors in behavioral phenotyping. The EUMORPHIA SOPs described here are an important start-point for the ongoing development of increasingly robust phenotyping platforms and their application in large-scale, multicentre mouse phenotyping programs.

Layer-specific excitatory circuits differentially control recurrent network dynamics in the neocortex

In the absence of external stimuli, the mammalian neocortex shows intrinsic network oscillations. These dynamics are characterized by translaminar assemblies of neurons whose activity synchronizes rhythmically in space and time. How different cortical layers influence the formation of these spontaneous cellular assemblies is poorly understood. We found that excitatory neurons in supragranular and infragranular layers have distinct roles in the regulation of intrinsic low-frequency oscillations in mice in vivo. Optogenetic activation of infragranular neurons generated network activity that resembled spontaneous events, whereas photoinhibition of these same neurons substantially attenuated slow ongoing dynamics. In contrast, light activation and inhibition of supragranular cells had modest effects on spontaneous slow activity. This study represents, to the best of our knowledge, the first causal demonstration that excitatory circuits located in distinct cortical layers differentially control spontaneous low-frequency dynamics.

Cognitive aging in zebrafish.

Background Age-related impairments in cognitive functions represent a growing clinical and social issue. Genetic and behavioral characterization of animal models can provide critical information on the intrinsic and environmental factors that determine the deterioration or preservation of cognitive abilities throughout life. Methodology/Principal Findings Behavior of wild-type, mutant and gamma-irradiated zebrafish (Danio rerio) was documented using image-analysis technique. Conditioned responses to spatial, visual and temporal cues were investigated in young, middle-aged and old animals. The results demonstrate that zebrafish aging is associated with changes in cognitive responses to emotionally positive and negative experiences, reduced generalization of adaptive associations, increased stereotypic and reduced exploratory behavior and altered temporal entrainment. Genetic upregulation of cholinergic transmission attenuates cognitive decline in middle-aged achesb55/+ mutants, compared to wild-type siblings. In contrast, the genotoxic stress of gamma-irradiation accelerates the onset of cognitive impairment in young zebrafish. Conclusions/Significance These findings would allow the use of powerful molecular biological resources accumulated in the zebrafish field to address the mechanisms of cognitive senescence, and promote the search for therapeutic strategies which may attenuate age-related cognitive decline.

Lithium rescues synaptic plasticity and memory in Down syndrome mice

Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the multifactorial context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients.

Autism-related behavioral abnormalities in synapsin knockout mice.

Highlights ► Deletion of Syn isoforms widely impairs social behavior. ► SynII−/− mice display impaired social interaction, novelty and recognition. ► SynI−/− and SynII−/− mice are characterized by increased social dominance. ► Young and adult SynI−/− and SynIII−/− mice exhibit deficits in social transmission of food preference. ► Social deficits in SynI−/− and SynII−/− mice appear before the onset of epilepsy.

An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy.

SUMMARY Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, GarsC201R, with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The GarsC201R mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons.

Differential effects of genotoxic stress on both concurrent body growth and gradual senescence in the adult zebrafish

Among vertebrates, fish and mammals show intriguing differences in their growth control properties with age. The potential for unlimited or indeterminate growth in a variety of fish species has prompted many questions regarding the senescent phenomena that appear during the aging process in these animals. Using zebrafish as our model system, we have attempted in our current study to examine the growth phenomena in fish in relation to the onset of senescence‐associated symptoms, and to evaluate the effects of genotoxic stress on these processes. We observed in the course of these analyses that the zebrafish undergoes continuous growth, irrespective of age, past the point of sexual maturation with gradually decreasing growth rates at later stages. Animal population density, current body size and chronological age also play predominant roles in regulating zebrafish growth and all inversely influence the growth rate. Interestingly, the induction of genotoxic stress by exposure to ionizing radiation (IR) did not adversely affect this body growth ability in zebrafish. However, IR was found to chronically debilitate the regeneration of amputated caudal fins and thereby induce high levels of abnormal fin regeneration in the adult zebrafish. In addition, by resembling and mimicking the natural course of aging, IR treatments likewise enhanced several other symptoms of senescence, such as a decline in reproductive abilities, increased senescence‐associated β‐galactosidase activity and a reduction in melatonin secretion. Our current data thus suggest that during the lifespan of zebrafish, the onset of senescence‐associated symptoms occurs in parallel with continuous growth throughout mid‐adulthood. Moreover, our present findings indicate that genotoxic DNA damage may play a role as a rate‐limiting factor during the induction of senescence, but not in the inhibition of continuous, density‐dependent growth in adult zebrafish.

Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features.

The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults.

TAAR1 Modulates Cortical Glutamate NMDA Receptor Function

Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, also play an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high-o5rder cognitive processes. TAAR1-selective ligands have shown potential antipsychotic, antidepressant, and pro-cognitive effects in experimental animal models; however, it remains unclear whether TAAR1 can affect PFC-related processes and functions. In this study, we document a distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that the development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions.