Development of the cerebral cortex in health and disease

Our research focusses on GABAergic interneurons and aims to answer four general questions:

How is neuronal diversity generated in the cerebral cortex?

One major goal of neuroscience is to understand how brain function emerges through the assembly of specific neuronal circuits. Elucidating how a small pool of neural progenitors generates the vast diversity of neuronal types in the CNS remains a fundamental question, since the different types of neuron — and their specific connectivity — are the basis for information processing. This problem is particularly challenging in the cerebral cortex, where dozens of different types of neuron converge during development to establish circuits which adopt distinct configurations across different areas and, most prominently, species.

Work from several laboratories, including ours, has provided evidence suggesting that interneuron diversity emerges from the differential specification of progenitor cells, which are grouped in largely non-overlapping progenitor domains. We are currently performing fate-mapping studies of specific progenitor domains in the subpallium to identify the precise origin of the different types of interneuron. In addition, we are performing single-cell transcriptomic and epigenetic studies aimed at defining the molecular signatures underlying the specification of interneuron diversity.

neurochemical characteristics. Cortical interneurons originate from the subpallium, the region of the telencephalon that also give rise to the basal ganglia and the amygdala, among other structures. Genetic and fate mapping studies –primarily in the mouse– have revealed that most cortical interneurons are born in three regions of the subpallium, the medial ganglionic eminence (MGE), the caudal ganglionic eminence (CGE), and the preoptic area (POA). Work from several laboratories, including ours, has provided evidence suggesting that interneuron diversity in the telencephalon emerges as a consequence of the differential specification of progenitor cells, which are grouped in largely non-overlapping progenitor domains. We are currently performing additional fate mapping studies of specific progenitor domains in the subpallium to identify the precise origin of interneurons. In particular, we are developing new methods to trace the progeny of individual progenitor cells within the subpallium, with the aim of identifying the fate and destiny of clonally-related interneurons.

How do interneurons integrate into specific cortical circuits?

The neocortex is organised on its radial dimension in six layers containing two major classes of neurons, excitatory glutamatergic pyramidal cells and inhibitory gamma-aminobutyric acid-containing (GABAergic) interneurons. Cortical columns may well represent a fundamental unit of cortical organisation, but the mammalian neocortex is not uniform. Indeed, the neocortex consists of discrete functional areas that are characterised by distinctive cytoarchitectonical features.

Previous studies have shown that the diversity of cortical interneurons varies substantially between cortical layers and areas. Although inhibitory circuits follow some general organisation principles across cortical areas, recent work indicates that the abundance of specific inhibitory connectivity motifs varies between regions. We are investigating to what extent distinct patterns of inhibitory connectivity may accompany, and perhaps even determine, the functional specialisation of cortical areas. These heterogeneous patterns of distribution would be sculpted by developmental mechanisms such as programmed cell death, aimed at adjusting the ratio of pyramidal cells and interneurons across different cortical areas.

What is the role of cortical interneurons in neural plasticity?

The balance between synaptic excitation and inhibition is critical for cortical function, and its disruption has been associated with several developmental neuropsychiatric conditions such as autism or schizophrenia. Although pyramidal cells may have very different levels of activity depending on the behavioural state and their specific engagement into particular neural assemblies, individual neurons show relatively stable ratios of excitation and inhibition caused by the prominent capability of interneurons to compensate for changes in the firing of pyramidal cells.

We are investigating how cortical interneurons regulate the adaptation of neural circuits to experience by controlling the connectivity between neurons. For example, the dynamic reconfiguration of PV+ fast-spiking basket cells in response to dynamic changes in network conditions has been linked to neural plasticity induced by recent experience. We have found that changes in the subcellular location of the transcription factor Etv1 allows these interneurons to dynamically adjust their excitability in response to changes in network activity.

How does disruption of interneuron development lead to disease?

Multiple lines of evidence support the hypothesis that cortical interneuron dysfunction plays a critical role in the pathophysiology of severe neurodevelopmental disorders such as epilepsy, autism and schizophrenia. For example, developmental disruption of the normal connectivity of PV+ interneurons leads to an abnormal increase in cortical excitability and abnormal synchrony, which may underlie the cognitive deficits observed in schizophrenia.

We are investigating the function of disease susceptibility genes such as ERBB4 and TSC2 in the development and function of cortical circuits. In particular, we are studying how the proteins encoded by these genes control synaptic development and plasticity. We are also performing electrophysiological and calcium imaging experiments in vivo to investigate how synaptic impairment caused by the deficiency of these genes leads to abnormal behaviour. Ultimately, we would like to understand whether multiple disease susceptibility genes converge in the regulation of interneuron wiring during development.