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Maladaptive Compensatory Plasticity in Developing Cortical Circuits

Award Number: R01NS109916
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Maladaptive Compensatory Plasticity in Developing Cortical Circuits - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$7 )
2025	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	9/9/2025	NON-COMPETING CONTINUATION	-$7
2025	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = -$7

Issue Date FY: 2023 ( Subtotal = $355,469 )
2023	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/30/2023	NON-COMPETING CONTINUATION	$35,547
2023	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/6/2022	NON-COMPETING CONTINUATION	$319,922
														Subtotal = $355,469

Issue Date FY: 2022 ( Subtotal = $391,588 )
2022	2022	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	12/3/2021	SUPPLEMENT FOR EXPANSION	$36,119
2022	2022	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	3/24/2022	NON-COMPETING CONTINUATION	$36,399
2022	2022	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/26/2021	NON-COMPETING CONTINUATION	$319,070
														Subtotal = $391,588

Issue Date FY: 2021 ( Subtotal = $427,705 )
2021	2021	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/12/2021	NON-COMPETING CONTINUATION	$42,771
2021	2021	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/14/2020	NON-COMPETING CONTINUATION	$384,934
														Subtotal = $427,705

Issue Date FY: 2020 ( Subtotal = $391,588 )
2020	2020	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	7/31/2020	SUPPLEMENT FOR EXPANSION	$36,119
2020	2020	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/20/2019	NEW	$355,469
														Subtotal = $391,588

Grand Total All Awards = $1,566,343

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Maladaptive Compensatory Plasticity in Developing Cortical Circuits

Award Number: R01NS109916

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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