Late maturation of GABAB synaptic transmission in area CA1 of the rat hippocampus
Introduction
The inhibitory neurotransmitter GABA acts via two separate classes of postsynaptic receptors: ionotropic GABAA/C receptors which mediate fast Cl− conductances and metabotropic GABAB receptors which are coupled to G-proteins and activate slow K+ conductances (for review see Bowery, 1993, Kerr and Ong, 1995). Due to their dissimilar mode of activation, ionotropic versus metabotropic, the time course of these two types of inhibitory postsynaptic currents are very different. This indicates that GABAA/C and GABAB receptors play distinct roles in mediating postsynaptic inhibition in the CNS. There is also evidence to suggest that GABAA and GABAB receptors may be activated by different populations of inhibitory neurons (Misgeld et al., 1995, Nurse and Lacaille, 1997a), which would indicate a further specialization and greater versatility of inhibitory function. In addition, GABAB receptors are also located on presynaptic terminals and involved in presynaptic inhibition of transmitter release (Bowery et al., 1980, Lanthorn and Cotman, 1981, Bowery, 1993, Misgeld et al., 1995).
Both GABAA and GABAB receptors are present during embryogenesis. GABA plays an active role in neurite outgrowth and synaptogenesis of neurons in culture (Spoerri, 1988, Behar et al., 1996). In situ, the number of GABAB receptors peaks in a region-specific manner during the first 1–2 weeks postnatal (Turgeon and Albin, 1994). Even though the number of GABAB receptors is maximal during early postnatal development, GABAB-mediated inhibition is not always fully mature at this stage. In addition to varying across brain regions, the time course of maturation differs for pre- and postsynaptic GABAB receptors. Presynaptic GABAB receptors mature earlier and are functional early in postnatal life (Gaiarsa et al., 1995b). In the hippocampal CA3 region, presynaptic GABAB receptors can be activated by the agonist baclofen to inhibit transmitter release at birth. However, GABAB-mediated paired-pulse depression, characteristic of mature inhibitory synapses, is not observed during the first postnatal week (Caillard et al., 1998). The absence of paired-pulse depression in immature animals, when presynaptic GABAB receptors can be activated by agonists, may be due to reduced levels of transmitter release at synapses of immature animals (Caillard et al., 1998). In contrast, in somatosensory cortex, GABAB-mediated paired-pulse depression is present after the first postnatal week (Fukuda et al., 1993).
Postsynaptic GABAB inhibition generally develops later than presynaptic inhibition, and again with a time course that varies across different brain regions. In cultured embryonic hypothalamic neurons, postsynaptic GABAB inhibition is present after 5 days in vitro (Obrietan and Van Den Pol, 1998). In the hippocampal CA3 area, postsynaptic GABAB inhibition can be observed in pyramidal cells at about postnatal (P) day 6 (Swann et al., 1989; Ben-Ari et al., 1994). In contrast, in the neocortex, postsynaptic GABAB inhibition matures only after 2–3 weeks postnatal (Luhmann and Prince, 1991, Fukuda et al., 1993).
In the hippocampal CA1 area, the development of GABA inhibition is delayed relative to that in the adjacent CA3 region (Janigro and Schwartzkroin, 1988, Swann et al., 1989). Although some have reported biphasic inhibitory postsynaptic potentials in pyramidal cells at around P9 in the rat (Swann et al., 1989), others did not observe hyperpolarizing postsynaptic GABAB responses until P30–35 in rabbits (Janigro and Schwartzkroin, 1988). Thus, it still remains unclear when postsynaptic GABAB transmission develops in the CA1 region of the rat hippocampus. Since studies aimed at determining GABAB synaptic mechanisms at the single cell level in the CA1 hippocampus tend to use whole cell recordings and single cell stimulation in young animals to aid neuronal visualization with infra-red videomicroscopy (Ouardouz and Lacaille, 1997), it is important to establish the developmental time course of GABAB synaptic transmission in this region. To address this issue, we recorded GABAB postsynaptic currents using whole cell voltage clamp techniques from CA1 pyramidal cells in hippocampal slices from rats of different postnatal ages. GABAB currents were elicited in isolation by electrical stimulation in the presence of antagonists of ionotropic glutamate and GABAA receptors, or by bath application of the GABAB agonist baclofen. Part of this work was previously presented in abstract form (Nurse and Lacaille, 1997b).
Section snippets
Methods
All chemicals were obtained from Sigma, unless indicated otherwise. Transverse hippocampal slices were obtained from male Sprague–Dawley rats of three different age groups 12–14, 22–24 and 35–45 days postnatal (P) (mean weights±S.D.: 28.86±0.7; 59.03±7.0; and 169.86±18.46 g, respectively). Animals were anesthetized with halothane prior to decapitation. The brain was removed from the skull and submerged in cold ACSF (in mM): 124 NaCl; 5 KCl; 1.25 NaH2PO4; 2 MgSO4; 2 CaCl2; 26 NaHCO3 and 10
Results
A total of 36 pyramidal cells were recorded from 36 hippocampal slices obtained from 29 animals. Fourteen cells were from adults (P35–45), 11 cells from P22–24 animals, and 11 cells from P12–14 animals. There was no significant difference between groups in mean series resistance (16.7±5.3 MΩ in P12–14; 17.6±5.5 MΩ in P22–24; 17.5±6.6 MΩ in P35–45) and whole cell capacitance (14.3±4.2 pF in P12–14; 18.2±8.7 pF in P22–24; 14.4±6.9 pF in P35–45).
Discussion
We have shown using whole cell voltage clamp recordings that the development of GABAB synaptic transmission is delayed and occurs gradually during the third to fifth postnatal week in area CA1 of the rat hippocampus. At 2 weeks postnatal (P12–14), the peak conductance of pharmacologically-isolated GABAB IPSCs and of baclofen currents was approximately 10% of adult values. After 3 weeks postnatal (P22–24), the magnitude of both GABAB IPSCs and baclofen currents was near 50–60% of adult values.
Acknowledgements
This work was supported by the Medical Research Council of Canada (J.-C.L.), the Fonds de la Recherche en Santé du Québec (FRSQ; J.-C.L.), a Research Center grant from the Fonds pour la Formation de Chercheurs et l’Aide à la Recherche (FCAR) to the Groupe de Recherche sur le Système Nerveux Central and an Équipe de Recherche grant from the FCAR (J.-C.L.). S.N. was supported by postdoctoral fellowships from the Heart and Stroke Foundation of Canada and the FRSQ. The authors wish to thank Dr W.
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