Our laboratory is exploring cell biological mechanisms underlying formation and plasticity of neuronal synapses in development, physiological states, and disorders. Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific impairment of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation – inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.

Sensations, thoughts, and actions are dynamic events that require the brain to encode the passage of time. For many tasks, such as playing music or sports, accurate execution requires the precise estimation of time intervals in the range of milliseconds to seconds. Nevertheless, how neuronal elements within brain circuits represent “time” is not understood. The cerebellar cortex is a prototypical brain circuit important for fine-tuning precise motor and cognitive behaviors on the subsecond time scale. Synaptic connections between neurons change their strength dynamically during brief bouts of activity, and we hypothesize that they could, therefore, act as a cellular substrate for encoding time within neural networks. I will summarize the theoretical underpinning of how diverse short-term synaptic plasticity can act as a substrate for a biological clock and experimental evidence supporting the role of dynamic synapses in sculpting neural dynamics within the cerebellum.

Information is transmitted between brain regions through the release of neurotransmitters from longrange projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein coupled receptor (GPCRs) pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision, or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumerilii ciliary opsin (PdCO) is an efficient, versatile, light-activated bistable GPCR that can suppress synaptic transmission in mammalian neurons with high temporal precision in-vivo. PdCO has superior biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping.