Role of VGF in cortical PV+ interneuron interconnectivity

What makes the brain special is that, unlike a computer, it adapts to changes or damage by modifying its connections, essentially re-wiring itself. Without this ability, known as brain plasticity, we would not be able to develop from infancy through to adulthood or recover from brain injury.

Neural networks typically consist of excitatory and inhibitory cells, and maintaining a proper balance between excitation and inhibition is critical for normal brain function. Many forces continuously perturb the balance between excitation and inhibition, from regular developmental changes to pathological alterations. Even the process of learning is known to alter this balance. Despite all these pressures, our brains manage - most of the time - to compensate for these changes and maintain a stable function. At the level of individual neurons and networks, this is due to a form of brain plasticity known as homeostatic plasticity, which is based on a simple rule: increasing a neuron's activity leads to changes in its connections or electrical properties aiming to reduce this activity and vice-versa, which ensures that neurons function within an optimal range.

In this project, we aim to investigate the mechanisms regulating homeostatic plasticity in the mouse cerebral cortex's main population of inhibitory neurons. These cells, which can be distinguished from other neurons by the expression of the calcium-binding protein parvalbumin (PV), guard cortical networks against runaway excitation, synchronise excitatory neurons, and are critically involved in learning. We have recently found that PV interneurons respond to changes in their activity by remodelling the inhibitory connections they receive from other PV interneurons. This process requires the function of the neuropeptide-encoding gene Vgf. In this project, we will: (1) study the cellular dynamics underlying the change in the number of synapses, (2) determine the specific VGF-derived peptides involved in synapse remodelling, and (3) identify the putative receptor mediating the function of VGF-derived peptides in PV+ interneurons.

We anticipate that elucidating the mechanisms modulating homeostatic plasticity in cortical PV inhibitory neurons will increase our understanding of their role in learning and memory and their involvement in the pathophysiology of neurodevelopmental disorders.

Brain plasticity enables individuals to modulate behaviours by learning from experience throughout life. Although the mechanisms regulating the plasticity of individual synapses have been analysed in substantial detail, the contribution of specific neuronal populations and networks to this process still needs to be better understood.

Recent studies have shown that experience modulates adult learning by influencing the molecular state and connectivity of parvalbumin-expressing (PV+) interneurons, the most abundant subclass of inhibitory neurons in the cerebral cortex. The maturation state of PV+ interneurons has also been implicated in critical period plasticity, which is essential for the development of mature functional properties in the brain. The mechanisms through which PV+ interneurons contribute to such a diverse range of functions remain unclear.

PV+ interneurons are widely distributed through the cortex and provide local feedforward and feedback inhibition onto principal excitatory neurons, from which they also receive their main inputs. Networks of excitatory and inhibitory neurons are balanced through homeostatic mechanisms that ensure they function within an optimal range. Previous studies have shown that excitatory neurons in the cerebral cortex adapt the inhibition they receive from PV+ interneurons in a similar proportion to their excitation. In contrast, the mechanisms through which PV+ interneurons adapt to changes in network activity have not been identified.

We have recently discovered that Vgf (non-acronymic) mediates the dynamic remodelling of inhibitory connections among cortical PV+ interneurons. In this project, we propose experiments to decipher how this neuropeptide-encoding gene regulates this process.