Developmental disorders including Autism Spectrum Disorders and Intellectual Disability can lead to reduced cortical activity. Paradoxically, these same disorders also greatly increase the risk for developing seizures. Homeostatic plasticity compensates for reduced activity by increasing overall gain within cortical circuits. But these normally beneficial mechanisms can have maladaptive effects, especially during critical periods of circuit formation. For example, activity blockade in vivo in rat or mouse neocortex, induces seizures, but only if deprivation is prolonged and occurs early. Here we explore the mechanisms underlying this Maladaptive Compensatory Plasticity (MCP) in neocortical slice culture. Activity blockade qualitatively changes network activity, and changes persist when activity is restored. There is a dramatic shift in the balance between excitation and inhibition following early, but not later deprivation. In contrast, changes in cellular excitability occur at both ages.
Aim 1 will identify the critical physiological features of MCP, that separate it from normal homeostatic plasticity. By blocking activity in single neurons, and varying the timing of activity blockade, we will distinguish cell autonomous from network effects, and determine which are critical for persistent MCP. Using Array Tomography and paired recording, we ask whether induction of MCP alters the number of functional excitatory and inhibitory synapses.
Aims 2 and 3 examine the transcriptional and epigenetic mechanisms of MCP.
In Aim 2 we develop the novel idea of push/pull transcriptional regulation of homeostatic plasticity. We identify a pair of closely related transcription factors (TFs) that are potently and progressively upregulated during blockade of activity. Intriguingly, these TFs are part of a pathway that opposes compensatory plasticity, since compensatory responses are exaggerated when they are knocked out. Finally, in Aim 3, we test the hypothesis that MCP is driven by a lasting change in the chromatin accessibility of cortical neurons. Together these studies may identify new strategies for mitigating maladaptive consequences of normally beneficial plasticity mechanisms.
Developmental disorders are frequently associated with reduced brain activity and, paradoxically, with increased risk of epilepsy. This may, in part, be caused by overactive plasticity mechanisms that normally maintain appropriate levels of brain activity. Understanding negative consequences of overactive plasticity mechanisms may help prevent or treat this problem.
