Development of different receptor types and functions during postnatal development

During early postnatal life, there are large changes in the distributions and thus functionality of a number of different receptor types, which has very important implications for neuronal excitability and synaptic plasticity throughout postnatal development. In several regions of the brain, it has been observed that muscarinic receptors develop in number and connectivity to secondary effector systems over the first few weeks of life. In particular, immunocytochemical analyses have shown that numbers of muscarinic receptors increase over the first two weeks in the parietal cortex (Buwalda et al., 1995), but in contrast, the frontal cortex appears to display a level of acetylcholine receptor density which commences at a relatively high level, and then gradually declines towards adulthood (Araki et al., 1996). This same study indicated that levels of cholinergic receptors in the hippocampus were fully developed at a very early age, a finding which was echoed by Reece & Schwartzkroin (1991), who discovered that electrophysiological responses to acetylcholine and carbachol (i.e. membrane depolarization and input conductance decrease measured in neurones from hippocampal brain slices) of rats of as little as two days of age were almost identical to those recorded in neurones of adult animals. This is not surprising considering the proposed involvement of the cholinergic system in learning and formation of memories, processes which are traditionally connected with the cortex and hippocampus.

Neuronal excitability in general is heavily influenced by the GABAergic system, which traditionally has an inhibitory action on cells. There are quite profound changes in GABA receptor density and function during the initial stages of development, in marked contrast to the cholinergic system. Again according to Araki et al. (1996), receptor

autoradiography indicated a wide distribution of GABA^ receptors in various areas of the cortex and hippocampus around the third week of postnatal life, steadily declining towards adulthood. In the hippocampus, however, a paradoxical excitatory action of GABA^ occurs in localised neurones during the first 8 postnatal days, resulting in giant GABA­ ergic depolarizing synaptic potentials, which (as well as spontaneous activity in these neurones) can be completely blocked by application of bicuculline (for review see Cherubini et al., 1991). This is in contrast to the adult situation where bicuculline actually

enhances the EPSP and causes spontaneous inter-ictal activity (Forti et al., 1997).

In the hippocampus, there is (in contrast to the development of the GABA^ receptor system) a definite postnatal alteration in the GABAg receptor system. The first indication of this was the discovery that in immature rats, the depolarizing EPSP was rather larger than that seen in adult neurones, and the late slow IPSP was completely absent in the young animal slices. This was accompanied by a depolarizing response to the compound 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol (TRIP) in immature neurones, which in adult cells, traditionally resulted in a membrane hyperpolarization (in retrospect, almost certainly by acting on GABAg receptors, although this was not inferred in the report; Mueller et al., 1984; c.f. the action of the GABAg agonist baclofen; Newberry & Nicoll, 1984). Later experiments showed that paired pulse depression (a measure of presynaptic autoreceptor activity) is absent in neonatal animals, indicating that the presynaptic autoreceptor activity of GABAg was missing (Gaiarsa et al., 1995 (possibly due to an early postnatal lack of GABAergic synaptic density; Rozenberg et al.,

1989). There is also a developmental change in GABAg receptor-mediated inhibition in cortical neurones, specifically studied in the somatosensory cortex of the rat. It was found that around postnatal day 7, there was no difference in paired pulse depression compared

with adult animals, indicating that presynaptic GABAg receptor activity was in place at this age. However, it was not until after postnatal day 22 that GABAg-mediated slow IPSPs were observed (Fukuda et al., 1993). It also appears that the GABAg-mediated slow IPSP was reduced in recordings taken firom immature (between P14-P22) olfactory cortical cells (see later; Postlethwaite et al., 1998).

Other receptor systems also undergo developmental changes, but are unlikely to contribute as greatly towards synaptic plasticity and learning behaviour in the young animals. The synaptic NMDA receptors in rat hippocampus undergo modification, probably resulting fi*om a change in NMDA receptor subunit composition, over the first 5 weeks of life, demonstrated by EPSPs being larger in amplitude over this period (Kirson & Yaaii, 1996). As in the hippocampus, there may also be developmental changes in cortical NMDA receptor fimction. With this in mind, it appears that changes are not as profound as with the GABAergic system, since neocortical brain slice neurones exposed to a reduced extracellular magnesium concentration display a similar pattern of oscillatoiy activity to that seen in adult neurones, with only minor developmental modifications (Flint

et al., 1997). The electrophysiological responses to trans-AC?T> in hippocampal neurones also apparently do not change during the first weeks after birth, indicating that the metabotropic glutamate receptors responsible for excitation in postsynaptic cells do not alter in their fimction over this period; however, there is a change in metabotropic glutamate receptor stimulated PI turnover over this same period (Boss et al., 1992). Responses to serotonin also develop over the first three weeks of life in rat hippocampal neurones, adult-type responses being achieved during the third week (Segal, 1990). The adrenergic system, certainly in the hippocampus, appears to be ftmctional very soon after birth, electrophysiological effects of agonists seemingly attaining adult type characteristics

by the 7th postnatal day (Moudy & Schwartzkroin, 1992). There is apparently a large increase in dopamine receptor density and function in the rat frontal cortex between postnatal weeks 3 and 4, then slowly increasing to adult levels after this time period (Noisin & Thomas, 1988). It is not yet known how changes in all these latter receptor systems in the olfactory cortex may contribute towards hyperexcitability or epileptic conditions.