Research reportAMPA and NMDA receptor-mediated currents in developing dentate gyrus granule cells
Introduction
The hippocampal dentate gyrus (DG) is vital to normal learning and memory [21] and is implicated in neurodevelopmental disabilities such as epilepsy, schizophrenia, and autism [20], [30] as well as neurodegenerative disorders such as Alzheimer disease [24]. Granule cells (GCs) of dentate gyrus undergo postnatal neurogenesis in many mammalian species including humans [6], [10]. Both clinical and experimental data suggest that newly born GCs may contribute to functional recovery from brain injury of diverse etiologies [3], [18], [25], [34] and/or serve as a source of replacement for cells lost in disease [13], [32]. Thus, the study of GC integration in the hippocampal network is of potential therapeutic importance.
Because of postnatal neurogenesis and stratification within DG, GCs with staggered birthdates can be studied in situ over a narrow animal age epoch and even within a given hippocampal slice. Using patch clamp recordings of biocytin-filled GCs in rat hippocampal slices in the first postnatal month, we have previously shown that cells with input resistance (IR) ranging from 0.250 to 3.0 GΩ can be found within an anatomically restricted region in the middle third of the suprapyramidal limb, and that the cells with highest IR are the least mature by morphometric criteria such as dendritic length and degree of penetration of the dendritic arbor into the molecular layer [17], [19]. In a subsequent qualitative electrophysiologic study of very immature GCs (IR ≥ 1 GΩ) from young rat DG (postnatal days 5–12), we demonstrated a maturational progression of the response to medial perforant path stimulation that paralleled morphometric advances in cell age: glutamatergic currents were absent in the youngest cells, exclusively NMDA-mediated in somewhat older cells, and both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA-mediated in the oldest cells in the population [37]. In the present study, we examined GCs from 5- to 12-day rats (IR range 0.350–2.200 GΩ) that had both AMPA and NMDA-mediated currents. Using IR as an index of maturity, we examined the relative maturation of amplitude and kinetics of these currents, and determined the response of the NMDA currents to the selective NR2B antagonist ifenprodil.
Section snippets
Materials and methods
Hippocampal slices (300–350 μm) from Sprague–Dawley rats of both genders (6–12 days) were prepared as previously described [37] and were maintained at 35 °C for at least 30 min, allowed to cool to room temperature and transferred as needed to a small volume perfusion chamber (32 °C). ACSF composition was (in mM): NaCl 124, KCl 3, CaCl2 2.4, MgSO4 1.3, NaH2PO4 1.25, NaHCO3 26, and glucose 10 (gassed with 95% O2/5% CO2, pH = 7.4). Recording pipettes were pulled from borosilicate glass capillaries
Amplitude and kinetics of NMDA and AMPA currents
NMDA and AMPA currents were compared in 39 GCs (Table 1). In this population, IR ranged from 0.350 GΩ (most mature) to 2.200 GΩ (least mature), and RMP became more hyperpolarized with advancing cell maturity as we have previously shown [19]. Both NMDA and AMPA peak currents increased with advancing cell maturity (Fig. 1) with mean peak AMPA current ranging from −53.0 ± 17.5 to −434.0 ± 134.7 pA, and mean peak NMDA current ranging from 65.2 ± 19.3 to 336.8 ± 117.0 pA. The ratio of peak NMDA/AMPA
Discussion
Using input resistance (IR) as an indicator of cell maturity, we characterized developmental properties of evoked AMPA and NMDA EPSCs in GCs from early postnatal rat DG. We report that the peak amplitudes of both types of current increased with advancing cell age and that the NMDA/AMPA amplitude ratio reversed from >1 in younger cells to <1 in older cells. NMDA EPSCs showed a maturational decrease in rise time but no change in decay time, whereas AMPA EPSCs showed neither rise nor decay time
Acknowledgments
Northwestern University Buehler Center on Aging, Crown Family, Mr. and Mrs. William J. White (BLT); Open Hearts for Retarded Children (JFP).
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