The overall objective of this proposal is to determine the cellular mechanisms underlying the age-dependent modulation of prefrontal cortical (PFC) interneuronal circuits. Such developmental regulation is highly relevant to the pathophysiology of schizophrenia since converging findings stress interneuron deficits during development as a potential basis for this disorder. However, the link between how an early developmental dysregulation of neural circuits affects the developmental trajectory of cortical interneuron maturation remains unknown. The PFC is a good site for studying the role of cortical inhibitory circuits, since the PFC plays an important role in working memory and decision-making, functions that become impaired in schizophrenia. Our recently published work and preliminary studies indicate that PFC interneuronal activity is enhanced after puberty. This postpubertal/late adolescent facilitation is thought to be related to the delayed maturation of the mesocortical dopamine system and the enhanced facilitation of glutamatergic drive onto these GABAergic interneurons. If during development, such interneuronal activity does not become enhanced, PFC inhibitory control will be altered at maturity. Such impairment would be important for the onset of PFC cognitive deficits during the periadolescent transition as observed in schizophrenia and certain psychiatric disorders. Our central hypothesis is that normal maturation of PFC GABA interneuronal function results from two concurrent late adolescent events: (i) augmentation of glutamatergic drive onto PFC interneurons;(ii) acquisition of postsynaptic Ca2+dependent signaling mechanisms that enable the increased interneuron response to dopamine. Thus, the rationale for the proposed work is that the developmental dysregulation of glutamatergic inputs to the PFC will be sufficient to alter the normal trajectory of prefrontal interneuronal function.
Aim 1 will determine the cellular mechanisms that contribute to the developmental facilitation of PFC interneuronal activity.
Aim 2 will determine the impact of the developmental facilitation of PFC interneuronal function on mesocortical-induced synchronous activity.
Aim 3 will determine the anatomical origin of glutamatergic inputs that contribute to the late-adolescent facilitation of PFC GABA interneuron activity. Our prediction is that presynaptic facilitation of glutamatergic drive onto PFC interneurons dictates the normal maturation of dopamine control of PFC inhibitory transmission. Our results should lead to novel physiological and molecular strategies to target the presynaptic mechanisms underlying PFC interneuronal maturation that will increase cortical inhibitory transmission.

Public Health Relevance

This proposal is aimed to determine the cellular mechanisms underlying the age-dependent modulation of cortical activity, with focus on prefrontal cortical interneuronal circuits. Such developmental regulation is highly relevant to the pathophysiology of schizophrenia since converging findings stress interneuron deficits during development as a potential basis for this disorder. Thus, successful completion of the proposed application should lead to the discovery of conceptual, pharmacological and physiological tools capable of dissecting the role of inhibitory network underlying normal and abnormal periadolescent transition to adulthood, and to provide critical knowledge on how cognitive symptoms in schizophrenia emerge late in adolescence.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH086507-05
Application #
8644899
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Panchision, David M
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rosalind Franklin University of Medicine & Sci
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
North Chicago
State
IL
Country
United States
Zip Code
60064
Caballero, Adriana; Flores-Barrera, Eden; Cass, Daryn K et al. (2014) Differential regulation of parvalbumin and calretinin interneurons in the prefrontal cortex during adolescence. Brain Struct Funct 219:395-406
Thomases, Daniel R; Cass, Daryn K; Meyer, Jacqueline D et al. (2014) Early adolescent MK-801 exposure impairs the maturation of ventral hippocampal control of basolateral amygdala drive in the adult prefrontal cortex. J Neurosci 34:9059-66
Cass, D K; Flores-Barrera, E; Thomases, D R et al. (2014) CB1 cannabinoid receptor stimulation during adolescence impairs the maturation of GABA function in the adult rat prefrontal cortex. Mol Psychiatry 19:536-43
Lew, Sergio E; Tseng, Kuei Y (2014) Dopamine modulation of GABAergic function enables network stability and input selectivity for sustaining working memory in a computational model of the prefrontal cortex. Neuropsychopharmacology 39:3067-76
Caballero, Adriana; Thomases, Daniel R; Flores-Barrera, Eden et al. (2014) Emergence of GABAergic-dependent regulation of input-specific plasticity in the adult rat prefrontal cortex during adolescence. Psychopharmacology (Berl) 231:1789-96
Flores-Barrera, Eden; Thomases, Daniel R; Heng, Li-Jun et al. (2014) Late adolescent expression of GluN2B transmission in the prefrontal cortex is input-specific and requires postsynaptic protein kinase A and D1 dopamine receptor signaling. Biol Psychiatry 75:508-16
Cass, Daryn K; Thomases, Daniel R; Caballero, Adriana et al. (2013) Developmental disruption of gamma-aminobutyric acid function in the medial prefrontal cortex by noncontingent cocaine exposure during early adolescence. Biol Psychiatry 74:490-501
Thomases, Daniel R; Cass, Daryn K; Tseng, Kuei Y (2013) Periadolescent exposure to the NMDA receptor antagonist MK-801 impairs the functional maturation of local GABAergic circuits in the adult prefrontal cortex. J Neurosci 33:26-34
Caballero, Adriana; Diah, Kimberly C; Tseng, Kuei Y (2013) Region-specific upregulation of parvalbumin-, but not calretinin-positive cells in the ventral hippocampus during adolescence. Hippocampus 23:1331-6
Heng, Li-Jun; Markham, Julie A; Hu, Xiu-Ti et al. (2011) Concurrent upregulation of postsynaptic L-type Ca(2+) channel function and protein kinase A signaling is required for the periadolescent facilitation of Ca(2+) plateau potentials and dopamine D1 receptor modulation in the prefrontal cortex. Neuropharmacology 60:953-62

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