Abstract
TRPM4 is a Ca2+-activated non-selective cationic channel that conducts monovalent cations. TRPM4 has been proposed to contribute to burst firing and sustained activity in several brain regions, however, the cellular and subcellular pattern of TRPM4 expression in medial prefrontal cortex (mPFC) during postnatal development has not been elucidated. Here, we use multiplex immunofluorescence labeling of brain sections to characterize the postnatal developmental expression of TRPM4 in the mouse mPFC. We also performed electrophysiological recordings to correlate the expression of TRPM4 immunoreactivity with the presence of TRPM4-like currents. We found that TRPM4 is expressed from the first postnatal day, with expression increasing up to postnatal day 35. Additionally, in perforated patch clamp experiments, we found that TRPM4-like currents were active at resting membrane potentials at all postnatal ages studied. Moreover, TRPM4 is expressed in both pyramidal neurons and interneurons. TRPM4 expression is localized in the soma and proximal dendrites, but not in the axon initial segment of pyramidal neurons. This subcellular localization is consistent with a reduction in the basal current only when we locally perfused 9-Phenanthrol in the soma, but not upon perfusion in the medial or distal dendrites. Our results show a specific localization of TRPM4 expression in neurons in the mPFC and that a 9-Phenanthrol sensitive current is active at resting membrane potential, suggesting specific functional roles in mPFC neurons during postnatal development and in adulthood.
Highlights
The prefrontal cortex (PFC) is a highly-evolved brain area that participates in higher cognitive functions such as short-term memory, decision-making and executive function (Miller, 2000)
The high EGTA intracellular solution completely abolished the current (−9.1 ± 1.3 pA, p < 0.0001, one-way ANOVA) after break-in the whole-cell configuration (Figure 5F, blue). These results indicate that TRPM4 expression and TRPM4-like currents are present in pyramidal neurons of the medial prefrontal cortex (mPFC) from early postnatal developmental stages and this current is active in resting non-stimulated condition
We demonstrated that TRPM4 immunolabeling increases during postnatal development up to postnatal day 35 (P35), and that at all stages immunolabeling is restricted to the soma and proximal dendrites of the pyramidal neurons
Summary
The prefrontal cortex (PFC) is a highly-evolved brain area that participates in higher cognitive functions such as short-term memory, decision-making and executive function (Miller, 2000). Two mechanisms appear to be involved in persistent firing: reverberating circuits through recurrent synaptic connectivity (Wang, 1999; Teramae and Fukai, 2005; Okamoto and Fukai, 2009; Knauer et al, 2013) and the nature of intrinsic excitability as mediated by the expression and activity of different ion channels (McCormick et al, 2003; Tahvildari et al, 2008; Ben-Mabrouk and Tryba, 2010; Boehlen et al, 2013; Papoutsi et al, 2013). Transient Receptor Potential type Melastatin 4 (TRPM4) is a non-selective cation channel activated by [Ca2+]i, and that is permeable to monovalent cations, impermeable to divalent cations, and is thought to underlay the CAN current in many cells (Launay et al, 2002; Vennekens and Nilius, 2007; Guinamard et al, 2010)
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