Éliane Proulx1, Deepika Suri2, Scott P Heximer3, Vidita A Vaidya2, Evelyn K Lambe4. 1. Department of Physiology, University of Toronto, Toronto, Ontario, Canada. 2. Tata Institute of Fundamental Research, Mumbai, India. 3. Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Heart and Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada. 4. Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada. Electronic address: evelyn.lambe@utoronto.ca.
Abstract
BACKGROUND: The experience of early stress contributes to the etiology of several psychiatric disorders and can lead to lasting deficits in working memory and attention. These executive functions require activation of the prefrontal cortex (PFC) by muscarinic M1 acetylcholine (ACh) receptors. Such Gαq-protein coupled receptors trigger the release of calcium (Ca(2+)) from internal stores and elicit prolonged neuronal excitation. METHODS: In brain slices of rat PFC, we employed multiphoton imaging simultaneously with whole-cell electrophysiological recordings to examine potential interactions between ACh-induced Ca(2+) release and excitatory currents in adulthood, across postnatal development, and following the early stress of repeated maternal separation, a rodent model for depression. We also investigated developmental changes in related genes in these groups. RESULTS: Acetylcholine-induced Ca(2+) release potentiates ACh-elicited excitatory currents. In the healthy PFC, this potentiation of muscarinic excitation emerges in young adulthood, when executive function typically reaches maturity. However, the developmental consolidation of muscarinic ACh signaling is abolished in adults with a history of early stress, where ACh responses retain an adolescent phenotype. In prefrontal cortex, these rats show a disruption in the expression of multiple developmentally regulated genes associated with Gαq and Ca(2+) signaling. Pharmacologic and ionic manipulations reveal that the enhancement of muscarinic excitation in the healthy adult PFC arises via the electrogenic process of sodium/Ca(2+) exchange. CONCLUSIONS: This work illustrates a long-lasting disruption in ACh-mediated cortical excitation following early stress and raises the possibility that such cellular mechanisms may disrupt the maturation of executive function.
BACKGROUND: The experience of early stress contributes to the etiology of several psychiatric disorders and can lead to lasting deficits in working memory and attention. These executive functions require activation of the prefrontal cortex (PFC) by muscarinic M1 acetylcholine (ACh) receptors. Such Gαq-protein coupled receptors trigger the release of calcium (Ca(2+)) from internal stores and elicit prolonged neuronal excitation. METHODS: In brain slices of rat PFC, we employed multiphoton imaging simultaneously with whole-cell electrophysiological recordings to examine potential interactions between ACh-induced Ca(2+) release and excitatory currents in adulthood, across postnatal development, and following the early stress of repeated maternal separation, a rodent model for depression. We also investigated developmental changes in related genes in these groups. RESULTS:Acetylcholine-induced Ca(2+) release potentiates ACh-elicited excitatory currents. In the healthy PFC, this potentiation of muscarinic excitation emerges in young adulthood, when executive function typically reaches maturity. However, the developmental consolidation of muscarinic ACh signaling is abolished in adults with a history of early stress, where ACh responses retain an adolescent phenotype. In prefrontal cortex, these rats show a disruption in the expression of multiple developmentally regulated genes associated with Gαq and Ca(2+) signaling. Pharmacologic and ionic manipulations reveal that the enhancement of muscarinic excitation in the healthy adult PFC arises via the electrogenic process of sodium/Ca(2+) exchange. CONCLUSIONS: This work illustrates a long-lasting disruption in ACh-mediated cortical excitation following early stress and raises the possibility that such cellular mechanisms may disrupt the maturation of executive function.