Myrto Denaxa Research Group

• Mechanisms controlling the maturation of distinct interneuron populations.

Around 60% of cortical interneurons (cINs) are born in the Medial Ganglionic Eminence (MGE), a subdomain of the mammalian embryonic telencephalon, and include two major subtypes defined by the expression of the calcium binding protein Parvalbumin (PV) and the neuropeptide Somatostatin (SST). In the past, we and others have identified a molecular cascade governing MGE-derived IN development. At the top of this cascade is the transcription factor (TF) Nkx2.1, which is expressed transiently in MGE-derived IN progenitors, followed by the sequential and prolonged expression of Lhx6, Sox6 and Sip1. Although, this initial genetic pathway provided a framework to understand MGE-derived interneuron fate determination, we are far away from the complete picture. We lack almost any insight into late developmental events, which define the mature functional identity for both PV and SST-expressing IN populations. Such events are expected to occur during postnatal stages and most likely are dependent on intrinsic factors, as well as input from the environment. In agreement with this hypothesis we have recently identified the TF and genome-organizing protein Satb1, whose expression is activity-dependent, as a key maturation promoting factor for MGE-derived INs.

We wish to unravel the mechanisms controlling the maturation of PV and SST-expressing interneurons. We aim to determine:

1. How the gene landscape and electrophysiological profile for both IN subtypes is evolved at critical time points during their maturation process.

2. How the environment, in terms of sensory or intra-cortical activity input, affects MGE-derived IN maturation.

3. The role of Satb1 as an important regulatory node between the network input and genetic pathways that dictate IN postnatal development.

 

• Generating and studying animal models for Interneuropathies.

Interneuron anomalies have been shown to underlie a variety of neurodevelopmental disorders in humans, including epilepsy, autism spectrum disorders, intellectual disability and schizophrenia. It is well documented that such inhibitory defects associated with such Interneuropathies often arise as a consequence of genetic mutations that disrupt the function of genes critical for interneuron development and function. Interestingly, many of the genes linked to neuropsychiatric diseases in humans, are also expressed in developing cortical interneurons in mice. Furthermore, several animal models with mutations in genes controlling interneuron development, exhibit phenotypes, which replicate some of the characteristics of Interneuropathies. Therefore, the study of mouse strains with genetic defects that affect the function of cortical interneurons seems to be a powerful tool in our understanding of the pathogenesis and treatment of a variety of brain dysfunctions.

We have recently generated a series of transgenic mice, in which TFs that we have previously identified to be essential for the development of cortical interneurons, can be deleted in a stage and cell type specific manner. These mice have distinct defects on the assembly of GABAergic circuitry due to changes in the number and/or subtype properties of interneurons. We aim to functionally analyze our interneuron-specific mutant mouse lines, in order to understand better the wiring events that leads to the assembly of inhibitory networks, and translate this knowledge to new treatments of Interneuropathies.

 

To achieve our aims, we are using mouse genetics and a number of diverse state-of-the-art experimental techniques, from in vivo neuron tracing, transcriptional and electrophysiological characterization, to the application of specific protocols for in vivo sensory manipulation and in utero or intracranial injections for the administration of specific substances in vivo. In addition, we are exploiting the recently developed methodology of chemogenetics, as well as viral approaches, to modify the function or visualize cellular properties of specific neurons in vivo, in the context of the whole brain.