Decoding mPFC Plasticity Across Life Stages

About This Grant

The medial prefrontal cortex (mPFC) is a midline cortical region critical for cognition and implicated in neurodevelopmental disorders such as autism spectrum disorders (ASD). Developmental plasticity has been demonstrated in cortical regions associated with sensory function, but much less is known about this in mPFC. Developmental plasticity occurs during critical periods in which plasticity is enhanced, and as such is a period of time in which ongoing experiences shape the ultimate formation of mature functional circuits. Recent evidence suggests an adolescent critical period for mPFC, but the exact timing and underlying synaptic and molecular mechanisms are unclear. To investigate this, we developed a high-throughput assay to test a key form of plasticity, Long Term Potentiation (LTP), in the brain slices of the mouse mPFC. Using multielectrode recording arrays, we record local field potentials and from these extract current-source density (CSD) signals to clearly differentiate pre- and post-synaptic components. Our preliminary data show that while mPFC brain slices from juveniles fail to exhibit LTP, slices from older adolescents have robust LTP, with adult slices showing reduced plasticity. This aligns with the maturation of perineuronal nets (PNNs), specialized extracellular matrices that stabilize circuits by ‘freezing’ plasticity and contributing to mature circuit function. In Aim 1, we will rigorously define mPFC developmental plasticity by mapping LTP and PNN expression across development, which will refine the key time points for complementary in vivo experiments while minimizing animal use. In Aim 2, we will manipulate PNNs and neural activity to test their role in critical period regulation. By degrading PNNs or using Designer Drugs Exclusively Activated by Designer Drugs (DREADDs) to reduce inhibitory activity in the mPFC, we will assess whether the critical period can be reopened in adults. This research integrates high-throughput electrophysiology methods with molecular analyses to uncover mPFC critical periods. Understanding these mechanisms will not only provide insights into prefrontal development but also inform therapeutic strategies for disorders with altered plasticity, such as autism or schizophrenia. 1