Investigating dynamiCa++l mechanisms underlying cortical development and disease
Investigating activity-dependent processes during cortical neuronal assembly in development and disease
X-linked mosaicism and behavioral heterogeneity in Rett syndrome
Circuit mechanisms of attention dysfunction in Scn8a+/- mice: implications for epilepsy and neurodevelopmental disorders
How do Astrocytes Sculpt Synaptic Circuits?
From symptoms to circuits in Fragile X syndrome
Dysregulated Translation in Fragile X Syndrome
Counteracting epigenetic mechanisms in autism spectrum disorders
Role of ASD risk genes on maturation of frontal-sensory cognitive control circuit
Memory, learning to learn, and control of cognitive representations
Studying cortical development through the lens of autism spectrum disorders
Reward system function and dysfunction in Autism Spectrum Disorders
Genetics of migraine and the use of genetic mouse models
Translational Biomarkers in Preclinical Models of Neurodevelopmental Disorders
Synaptic alterations in the striatum drive ASD-related behaviors in mice
Mechanisms of sleep-seizure interactions in tuberous sclerosis and other mTORpathies
An intriguing, relatively unexplored therapeutic avenue to investigate epilepsy is the interaction of sleep mechanisms and seizures. Multiple lines of clinical observations suggest a strong, bi-directional relationship between epilepsy and sleep. Epilepsy and sleep disorders are common comorbidities. Seizures occur more commonly in sleep in many types of epilepsy, and in turn, seizures can cause disrupted sleep. Sudden unexplained death in epilepsy (SUDEP) is strongly associated with sleep. The biological mechanisms underlying this relationship between seizures and sleep are poorly understood, but if better delineated, could offer novel therapeutic approaches to treating both epilepsy and sleep disorders. In this presentation, I will explore this sleep-seizure relationship in mouse models of epilepsy. First, I will present general approaches for performing detailed longitudinal sleep and vigilance state analysis in mice, including pre-weanling neonatal mice. I will then discuss recent data from my laboratory demonstrating an abnormal sleep phenotype in a mouse model of the genetic epilepsy, tuberous sclerosis complex (TSC), and its relationship to seizures. The potential mechanistic basis of sleep abnormalities and sleep-seizure interactions in this TSC model will be investigated, focusing on the role of the mechanistic target of rapamycin (mTOR) pathway and hypothalamic orexin, with potential therapeutic applications of mTOR inhibitors and orexin antagonists. Finally, similar sleep-seizure interactions and mechanisms will be extended to models of acquired epilepsy due to status epilepticus-related brain injury.
The effects of maternal immune activation on early development in an outbred strain of mice
Gut-brain signaling as a driver of behavior and gene expression in a mouse model for autism spectrum disorder
Migraine: a disorder of excitatory-inhibitory balance in multiple brain networks? Insights from genetic mouse models of the disease
Migraine is much more than an episodic headache. It is a complex brain disorder, characterized by a global dysfunction in multisensory information processing and integration. In a third of patients, the headache is preceded by transient sensory disturbances (aura), whose neurophysiological correlate is cortical spreading depression (CSD). The molecular, cellular and circuit mechanisms of the primary brain dysfunctions that underlie migraine onset, susceptibility to CSD and altered sensory processing remain largely unknown and are major open issues in the neurobiology of migraine. Genetic mouse models of a rare monogenic form of migraine with aura provide a unique experimental system to tackle these key unanswered questions. I will describe the functional alterations we have uncovered in the cerebral cortex of genetic mouse models and discuss the insights into the cellular and circuit mechanisms of migraine obtained from these findings.
On the role of the ADNP gene in mice and man
Pitt-Hopkins Syndrome, mouse models, neurodevelopment, therapeutics
(Dys)regulation of the social brain
Dysregulation of mTOR Signaling Mediates Common Neurite and Migration Defects in Idiopathic and 16p11.2 Deletion Autism neural progenitors
Male-specific intracellular signaling and male bias in neurodevelopmental disorders
Sensory Processing and Arousal in Neurodevelopmental Disorders
Sex-Specific Brain Transcriptional Signatures in Human MDD and their Correlates in Mouse Models of Depression
Major depressive disorder (MDD) is a sexually dimorphic disease. This sexual dimorphism is believed to result from sex-specific molecular alterations affecting functional pathways regulating the capacity of men and women to cope with daily life stress differently. Transcriptional changes associated with epigenetic alterations have been observed in the brain of men and women with depression and similar changes have been reported in different animal models of stress-induced depressive-like behaviors. In fact, most of our knowledge of the biological basis of MDD is derived from studies of chronic stress models in rodents. However, while these models capture certain aspects of the features of MDD, the extent to which they reproduce the molecular pathology of the human syndrome remains unknown and the functional consequences of these changes on the neuronal networks controlling stress responses are poorly understood. During this presentation, we will first address the extent by which transcriptional signatures associated with MDD compares in men and women. We will then transition to the capacity of different mouse models of chronic stress to recapitulate some of the transcriptional alterations associated with the expression of MDD in both sexes. Finally, we will briefly elaborate on the functional consequences of these changes at the neuronal level and conclude with an integrative perspective on the contribution of sex-specific transcriptional profiles on the expression of stress responses and MDD in men and women.