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Neurogenetics and Synaptopathies

Principal investigator: Francisco Manuel Gomez Scholl , Ph.D.

Group research focus

Our research is focused on the study of the mechanisms that regulate synapse formation and function in normal conditions and their role in the onset of brain disorders, particularly autism and Alzheimer’s disease.

We are especially interested in the synaptic pathway mediated by neurexins and neuroligins, a trans-synaptic adhesion system that regulates the function of synapses. Within these aims, we perform experimental approaches that range from human genetics in patients with brain disorders and molecular and cellular neurobiology to behavioral assays in animal models.

Synapses and autism spectrum disorders

Induction of synaptogenesis in cultured neurons.

Induction of synaptogenesis in cultured neurons.

Using genetic approaches in patients with autism we identified mutations in the neurexin-1 beta gene that reduce the synaptic levels of the mutant proteins in cultured neurons. To analyze the role of neurexin dysfunction in the onset and maintenance of autism we generated transgenic βNrx1ΔC mice that express a mutant neurexin-1 beta protein selectively during late postnatal stages. Furthermore, the genetic strategy we developed allowed us to turn-off expression of mutant βNrx1ΔC protein at any developmental time, which facilitates reversion studies. We could demonstrate that altered neurexin function in postnatal brain impairs glutamatergic transmission and recapitulates autism-related behavior, such as increased repetitive behavior, impaired social interaction and exaggerated response to non-social olfactory cues. Notably, the autistic-like phenotype can be reversed at any time during adulthood when normal neurexin function is restored.

Alzheimer’s disease and synaptic genes

From human genetics to synapses.

From human genetics to synapses.

Alzheimer’s disease (AD) is an aging-related neurodegenerative disorder characterized by progressive memory loss of the patients. Based on their role at the synapse, we hypothesized that neurexins and neuroligins could mediate synaptic deficits associated with AD. In this line, we found that neurexins are proteolitically processed by presenilins (PS), plasma membrane proteins that are mutated in familial AD. Moreover, neurexin processing can be affected by familial AD-associated PS1 mutations. Using next-generation sequencing (NGS) in AD patients followed by functional validation we are searching for mutations in members of the neurexin-neuroligin pathway with patogenic effect in AD.

Objectives

The reversion of autism-related symptoms in animal models suggests that interventions aimed at boosting normal synaptic function might mitigate the behavioral deficits associated with autism in patients. We are developping experimental approaches to uncover the molecular mechanisms associated with the onset and reversion of autism-associated behavior using the validated βNrx1ΔC mouse model of autism. We believe that the characterization of the synaptic pathway responsible for the maintenance of the autism-related behavior can help identify molecular targets with therapeutic potential. The impact of presenilin-dependent neurexin processing and the role of pathogenic mutations in members of the neurexin-neuroligin pathway identified in Alzheimer’s disease are analyzed by the generation of cellular and in vivo approaches.

Ongoing collaborative research

Recent publications