Concurrent upregulation of postsynaptic L-type Ca2+ channel function and protein kinase A signaling is required for the periadolescent facilitation of Ca2+ plateau potentials and dopamine D1 receptor modulation in the prefrontal cortex

Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Rd., North Chicago, IL 60064, USA.
Neuropharmacology (Impact Factor: 5.11). 02/2011; 60(6):953-62. DOI: 10.1016/j.neuropharm.2011.01.041
Source: PubMed


Further understanding of how prefrontal cortex (PFC) circuit change during postnatal development is of great interest due to its role in working memory and decision-making, two cognitive abilities that are refined late in adolescence and become altered in schizophrenia. While it is evident that dopamine facilitation of glutamate responses occurs during adolescence in the PFC, little is known about the cellular mechanisms that support these changes. Among them, a developmental facilitation of postsynaptic Ca(2+) function is of particular interest given its role in coordinating neuronal ensembles, a process thought to contribute to maturation of PFC function. Here we conducted whole-cell patch clamp recordings of deep-layer pyramidal neurons in PFC brain slices and determined how somatic-evoked Ca(2+)-mediated plateau depolarizations change throughout postnatal day (PD) 25 (juvenile) to adulthood (PD 80). Postsynaptic Ca(2+) potentials in the PFC increase in duration throughout postnatal development. A remarkable shift from short to prolonged depolarizations was observed after PD 40. This change is reflected by an enhancement of L-type Ca(2+) channel function and postsynaptic PKA signaling. We speculate that such a protracted developmental facilitation of Ca(2+) response in the PFC may contribute to improvement of working memory performance through adolescence.

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    • "Ca ++ ions may trigger development of dendritic spines during adolescence (Lemieux et al., 2012). Ca ++ ions also prolong medial PFC pyramidal neuron depolarization during adolescence (Heng et al., 2011). In addition , lower expression of BK channels should increase dendritic excitability in neocortical pyramidal neurons (Benhassine and Berger, 2009). "
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    ABSTRACT: The medial prefrontal cortex (PFC) is involved in cognitive functions, which undergo profound changes during adolescence. This alteration of the PFC function derives from neuron activity, which, in turn, may depend on age-dependent properties and the expression of neuronal ion channels. BK-type channels are involved in controlling both the Ca++ ion concentration in the cell interior and cell excitability. The purpose of this study was to test the properties of BK currents in the medial PFC pyramidal neurons of young (18–22-day-old), adolescent (38–42-day-old) and adult (58–62-day-old) rats. Whole-cell currents evoked by depolarizing voltage steps were recorded from dispersed medial PFC pyramidal neurons. A selective BK channel blocker – paxilline (10 µM) – irreversibly decreased the non-inactivating K+ current in neurons that were isolated from the young and adult rats. This current was not significantly affected by paxilline in the neurons obtained from adolescent rats. The properties of single-channel K+ currents were recorded from the soma of dispersed medial PFC pyramidal neurons in the cell-attached configuration. Of the K+ channel currents that were recorded, ~90% were BK and leak channel currents. The BK-type channel currents were dependent on the Ca++ concentration and the voltage and were inhibited by paxilline. The biophysical properties of the BK channel currents did not differ among the pyramidal neurons isolated from young, adolescent and adult rats. Among all of the recorded K+ channel currents, 38.9%, 12.7% and 21.1% were BK-type channel currents in the neurons isolated from the young, adolescent and adult rats, respectively. Furthermore, application of paxilline effectively prolonged the half-width of the action potential in pyramidal neurons in slices isolated from young and adult rats but not in neurons isolated from adolescent rats. We conclude that the availability of BK channel currents decreases in medial PFC pyramidal neurons of adolescent rat
    Frontiers in Cellular Neuroscience 10/2013; 7:185. DOI:10.3389/fncel.2013.00185 · 4.29 Impact Factor
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    • "changes are consistent with reported variations in DA receptor binding sites during adolescence (Tarazi et al., 1998; Teicher et al., 1995), but they can also be due to changes in intracellular signaling cascades. Indeed, L-type calcium channel function and postsynaptic PKA signaling have been shown to mature during adolescence (Heng et al., 2011). Both L-type calcium channels and PKA signaling are important factors for D 1 –NMDA receptor interactions (Cepeda and Levine, 1998; Tseng and O'Donnell, 2004; Wang and O'Donnell, 2001). "
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    ABSTRACT: Many aspects of the dopamine (DA) system mature during adolescence. For example, the DA modulation of glutamate responses in the rat prefrontal cortex (PFC) acquires adult characteristics during late adolescence. In the striatum, D₁ receptors modulate NMDA responses, but whether this behaviorally important interaction matures during adolescence is not known. Here, we tested whether the D₁ agonist SKF38393 affects NMDA actions on nucleus accumbens medium spiny neuron (MSN) excitability in slices from juvenile and young adult rats. NMDA dose-dependently increased excitability in both age groups, and the D₁ agonist produced a marginal increase of MSN excitability. In juvenile slices, the most common interaction was a downregulation of NMDA effects on excitability by the D₁ agonist, whereas in most adult MSN, the D₁ agonist increased NMDA effects on MSN excitability. These results suggest that D₁-NMDA receptor interactions in the nucleus accumbens change during adolescence, a change that may result in different processing of reward functions during this critical developmental stage.
    Synapse 07/2012; 66(7):584-91. DOI:10.1002/syn.21544 · 2.13 Impact Factor
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    ABSTRACT: The peak in incidence for schizophrenia is during late adolescence for both sexes, but within this time frame the peak is both earlier and steeper for males. Additionally, women have a second peak in incidence following menopause. Two meta-analyses have reported that men have an overall ∼40% greater chance of developing schizophrenia than do women (Aleman et al., 2003; McGrath et al., 2004). These and other findings have led to the suggestion that ovarian hormones may be protective against schizophrenia. Less explored is the potential role of testosterone in schizophrenia, although disruptions in steroid levels have also been reported in men with the illness. The relationship between increased gonadal hormone release per se and peri-adolescent vulnerability for psychiatric illness is difficult to tease apart from other potentially contributory factors in clinical studies, as adolescence is a turbulent period characterized by many social and biological changes. Despite the obvious opportunity provided by animal research, surprisingly little basic science effort has been devoted to this important issue. On the other hand, the animal work offers an understanding of the many ways in which gonadal steroids exert a powerful impact on the brain, both shaping its development and modifying its function during adulthood. Recently, investigators using preclinical models have described a greater male vulnerability to neurodevelopmental insults that are associated with schizophrenia; such studies may provide clinically relevant insights into the role of gonadal steroids in psychiatric illness.
    Reviews in Endocrine and Metabolic Disorders 05/2011; 13(3):187-207. DOI:10.1007/s11154-011-9184-2 · 4.89 Impact Factor
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