# Maladaptive compensatory plasticity in developing cortical circuits

> **NIH NIH R01** · BRANDEIS UNIVERSITY · 2020 · $355,469

## Abstract

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. Multiple homeostatic plasticity mechanisms can compensate for reduced activity by increasing
excitatory synaptic transmission and cellular excitability, and/or by decreasing inhibitory synaptic transmission.
But these normally beneficial mechanisms can have maladaptive effects, especially when reduced activity is
prolonged and occurs early, during a critical period of circuit formation. For example, activity blockade in vivo in
rat or mouse neocortex, induces seizures, but only if it occurs early and for a prolonged period. Here we
explore the mechanisms underlying this Maladaptive Compensatory Plasticity (MCP) in cultured neocortical
slices. Activity blockade produces a qualitative change in subsequent synchronized activity that persists
following prolonged deprivation when activity is restored. This is accompanied by a dramatic shift in the
balance between excitation and inhibition. Physiological and imaging studies are consistent with a dramatic
change in synaptic connectivity. Aim 1 will identify the critical physiological features of MCP, that separate it
from normal homeostatic plasticity. By blocking activity in single neurons, and by varying the timing and
duration of activity blockade, we will distinguish cell autonomous from network effects, and determine which
are critical for persistent effects of MCP. Using synapse imaging techniques and paired recording, we ask
whether induction of MCP alters the number of functional excitatory and inhibitory synapses.
 Aims 2 develops 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. CRISPR-based manipulations will
be used to alter TF expression selectively in specific cell types. RNAseq will be used to identify candidate
targets, and chromatin assays will distinguish direct and indirect targets. Finally, we will initiate in vivo studies
to more directly test the role of homeostatic plasticity and its transcriptional regulation in audiogenic seizures.
Together these studies may identify new strategies for mitigating maladaptive consequences of normally
beneficial plasticity mechanisms.

## Key facts

- **NIH application ID:** 9896970
- **Project number:** 1R01NS109916-01A1
- **Recipient organization:** BRANDEIS UNIVERSITY
- **Principal Investigator:** Sacha B Nelson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,469
- **Award type:** 1
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896970

## Citation

> US National Institutes of Health, RePORTER application 9896970, Maladaptive compensatory plasticity in developing cortical circuits (1R01NS109916-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9896970. Licensed CC0.

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