Neural circuit assembly and brain disorders

Assembly of GABAergic synapses

The function of neural networks in the cerebral cortex of vertebrates relies on the interaction between two main classes of neurons, excitatory projection neurons and inhibitory interneurons. In these circuits, the output of excitatory neurons is fine-tuned and synchronised by the function of inhibitory neurons. Most notably, different classes of interneurons target different compartments of the pyramidal cells, the apical dendrites, the cell body, or even the axonal initial segment (AIS). Since the location of synaptic contacts largely determines their influence on the postsynaptic cell, it has been suggested that this elaborate organisation of inputs greatly increases the overall computational power of single neurons. One of the goals in my lab is to identify molecules involved in the formation of subcellular domain-restricted GABAergic synapses. To this end, we have carried out several unbiased genomic screens during comparing unique populations of interneurons that make synapses into different subcellular compartments. We have unveiled cell-specific molecular programs in cortical interneurons that emerge during the early wiring of these cells and underlie the specification of their connection patterns. In addition to the molecular codes controlling the subcellular targeting of inhibitory synapses, interneurons precisely target different pyramidal cell subnetworks. We are currently investigating the cellular and molecular mechanisms underlying the assembly of these inhibitory circuitries. Unraveling the mechanisms that control the precise spatial organization of synapse formation during development should have a broad impact, from understanding plasticity in the healthy brain to identifying wiring abnormalities in disease.

GABAergic circuitries and developmental disorders

Neuropsychiatric disorders, such as autism or schizophrenia, represent the leading source of disease burden in the developed world since begin early in life and contribute to lifelong incapacity or reduced longevity. Consequently, brain disorders will become an even greater public health challenge in the coming decades. Understanding the complex neurobiology underlying brain disorders is key for the development of new treatments. In this context, the development of new animal models that mimic some of the symptoms of these devastating diseases represents a major opportunity to expand the search for novel targets to treat neurodevelopmental disorders, such as schizophrenia. Increasing evidence suggest that impaired development of specific neuronal circuits in the cerebral cortex is at the basis of several neuropsychiatric conditions, including schizophrenia. In particular, cognitive dysfunction in schizophrenia is linked to a reduction in the power of gamma-band oscillations in the cerebral cortex, which are generated through the modulation of pyramidal cells by fast-spiking interneurons. Interestingly, fast-spiking interneurons and their connections seem to be particularly affected in schizophrenia. We have recently generated a genetic model with fast-spiking interneuron deficiency that mimics many anatomical, physiological and behavioural features of schizophrenia, including abnormal oscillatory activity and de-synchrony between hippocampus and prefrontal cortex. The network failure causes cognitive deficits and hyperlocomotion. We are developing this project in collaboration with Dr. Oscar Marín.