Layer 1 interneurons as master regulators of prefrontal cortex circuit development

The brain contains many hundreds of individual cell types which must be connected together to form a normal functional network. If this process occurs normally, it gives rise to our ability to learn, to sense, to move, to plan and to reason. In instances where this process fails it can give rise to devastating neurodevelopmental disorders, such as autism and schizophrenia. To understand brain development we must create a wiring diagram of the brain at different ages and figure out when and how it changes. This proposal aims to determine both by looking at how key cell types regulate circuit formation during precise periods of development. The when is important because brain maturation occurs at different speeds in different brain structures. The period of adolescence is linked to the emergence of our ability to engage in higher-level cognitive tasks such as abstract thought, logic and planning. This coincides with changes in the circuitry of a brain region called the prefrontal cortex. Although we have significant evidence to suggest that the prefrontal cortex changes during adolescence, we still do not understand how this occurs.

Based on previous studies by myself and others I predict that certain key cell types may function as master regulators of development within the prefrontal cortex. These cells are known as layer 1 interneurons and display unique connectivity patterns that allow them to control the activity of a huge number of cells within the local circuit. This connectivity is predicted to help layer 1 interneurons regulate the formation of connections, termed synapses, between individual components of the prefrontal cortex network. This suggests that if we disrupt the ability of L1 interneurons to perform their normal role in the network during key periods of prefrontal cortex development, such as adolescence, it will cause long-term changes to prefrontal cortex network formation and function. The potentially powerful influence of these cell types over a large number of neurons has led to my hypothesis that these cells function as master regulators of the rate and magnitude of prefrontal cortex local development.

In this BBSRC proposal I will test this hypothesis by combining an array of sophisticated genetic tools to either activate or silence the activity of L1 interneurons during adolescence and determine the impact on the local and long-range circuits of the prefrontal cortex. The findings that emerge from these studies will strengthen our understanding of the mechanisms behind normal brain development during healthy ageing. By shedding light on the potential of these novel cell types to regulate prefrontal cortex maturation, we will also reveal new therapeutic targets that could be used to control the maturation of prefrontal circuits in patients suffering from neurodevelopmental disorders, helping to restore normal network maturation and function. This work is therefore poised to make key advances in our understanding of the maturation of this important brain region.

Cortical development depends on the formation and refinement of synaptic connections between constituent neurons of both local and long-range circuits. These connections require synaptic activity to form, culminating in an adult cortex with remarkably precise and stereotyped patterns of connectivity. Normal circuit development depends on a population of cells termed GABAergic interneurons. Studies in sensory cortices reveal how a subpopulation of GABAergic cells, parvalbumin positive basket cells, regulate developmental plasticity in the thalamo-cortical system. However, we have limited understanding of the development of non-sensory regions, such as the prefrontal cortex (PFC). Moreover, the ability of other interneuron subtypes to control cortical development has not been explored. A subset of cortical interneurons that reside in layer 1 (L1 INs) have recently emerged as important regulators of cortical plasticity and function, via their ability to control the relative levels of excitation and inhibition within the local network. This includes a recently characterised population that act as upstream regulators of parvalbumin interneuron activity. This proposal will use a sophisticated array of optogenetic and chemogenetic tools to determine the role of L1 INs in the development of the rodent PFC. Using chemogenetics I will bi-directionally control the activity of genetically defined L1 IN populations during adolescence to determine the developmental impact of increasing or decreasing their activity. Combining Cre and Flp mouse lines with novel viral strategies I will determine how other genetically defined populations within the local circuit are impacted by L1 IN activity. Finally, using optogenetics I will determine how L1 INs influence the maturation of thalamo-cortical networks that are critical for normal PFC function. These studies will determine if L1 INs are important for adolescent development and their downstream impact on local and long-range circuits.