The interactions of the various neurotransmitter systems in the hippocampal formation are numerous and not yet completely understood. The questions of which processes fail during aging and how do impaired transmitter systems affect other neurotransmitter functions is even harder to resolve. Even when considering a single neurotransmitter, several processes could be impaired during aging. For example, the synthesis of a neurotransmitter could be decreased, the transport of the neurotransmitter molecules to the axon terminals could be impaired, the release of the neurotransmitter from synaptic vesicles into the synaptic cleft could be hindered, the binding capacity or the number of (post-synaptic) receptors could be reduced, the receptor turnover rate can be changed,
receptor desensitization may occur, and the removal of the neurotransmitter from the synaptic cleft could be altered. However, lessened neurotransmitter contents might be compensated for, at least to an extent, by increased receptor binding potential or receptor numbers. Apart from altered chemical processes within neurons, neurotransmitter fibers themselves may undergo severe changes. Axons may degenerate and therefore (partly) deplete the hippocampal formation from certain neurotransmitters. In the following paragraphs, only changes of hippocampal afferents will be discussed. However, it should be kept in mind that the synthesis, transport, and release of neurotransmitters and the features of their receptors may also be altered during aging.
The principal cells of the hippocampal formation use glutamate as a neurotransmitter. The activity of the intrinsic hippocampal circuitry is modulated by other neurotransmitters, such as GABA, acetylcholine, serotonin, and noradrenaline. In the following paragraphs, the above-mentioned neurotransmitters systems in the hippocampal formation are shortly introduced. Swanson et al. (1987) and Kobayashi and Amaral (1999) gave extensive reviews on the distributions of these and other neurotransmitter systems in the rat and rhesus monkey hippocampal formation, respectively. The synaptic and non-synaptic interaction of these neurotransmitters are reviewed in detail by Vizi and Kiss (1998).
1.7.1. Glutamate
Glutamate acts as an excitatory neurotransmitter in the major pathways of the hippocampal formation (Fig. 1.4). Glutamatergic neurotransmission takes place almost exclusively across synapses. Principal neurons of layers II and III in the entorhinal cortex, the granule cells and the pyramidal cells of the hippocampus are all glutamatergic.
Principal cells of the hippocampus make also contact to GABAergic interneurons.
Relatively few studies have been conducted to study the relationship between glutamate and aging of the brain. However, consistent findings are a decrease in glutamate content and the decrease in the density of glutamatergic NMDA receptors with aging (Segovia et al., 2001).
1.7.2. GABA
GABA (g-amino butyric acid) is an inhibitory neurotransmitter. Virtually all hippocampal interneurons are GABAergic and they comprise about 10% of the total neuron population of the hippocampal formation. GABA participates mainly in synaptic interactions, i.e. it hardly acts by diffusion from varicosities. GABAergic interneurons mostly make synaptic contacts with principal cells (Fig. 1.4), however, to a smaller extent they innervate other interneurons. GABAergic interneurons that make synaptic contacts in the hippocampal formation are present in the hippocampal formation (ipsi- and contralateral), and in the medial septum and the diagonal band of Broca.
To date, it is not known with certainty whether GABAergic neurons disappear with aging. However, it is suggested that the GABAergic tone is compromised in aging, resulting in a loss of control of excitability and synchronization of the hippocampal principal cells (Vela et al., 2003).
1.7.3. Acetylcholine
Acetylcholine acts as an excitatory neurotransmitter. Cholinergic fibers in the hippocampal formation mainly arise from the medial septal nucleus and the nuclei of the diagonal band of Broca. A lesser portion of cholinergic innervation originates from the basal nucleus of Meynert. The varicose cholinergic fibers are widely distributed in the hippocampal formation, however, the distribution of fibers in rodents is slightly different from that in nonhuman primates and humans. Studies in rats showed that cholinergic fibers mainly terminate on principal neurons, and hardly on interneurons (Yamano and Luiten, 1989; Freund and Buzsaki, 1996). Acetylcholine is released from synapses and at nonsynaptic varicose sites (Fig. 1.4), however, it is not clear to which extent varicosities make synaptic contacts.
Figure 1.4
Simplified schematic diagram of the hippocampal architecture and its afferent pathways. Principal cells (white pyramidal cell) are glutamatergic; interneurons (white round cells) are GABAergic. A granule cell as the principal cell in the dentate gyrus receives glutamatergic input (perforant pathway) from the entorhinal cortex. A CA3 neuron as principal cell receives information from the mossy fibers. A CA principal neuron receives input from CA3 collaterals. Arrows indicate nonsynaptic release of neurotransmitter, small circles indicate synaptic transmission.
Abbreviations: CA: Cornu Ammonis; DG: dentate gyrus; Glu: glutamate; ACh: acetylcholine;
5-HT: 5-hydroxy-tryptamine = serotonin; NA: noradrenaline; GABA: g-amino butyric acid; M.S.
medial septum; R.N. raphe nucleus; L.C.: locus coeruleus.
Adapted from Vizi and Kiss (1998)
Acetylcholine has been ascribed an important role in processes of (spatial) learning and memory (Hortnagl and Hellweg, 1997). Cholinergic basal forebrain neurons have long been known to be susceptible to atrophy and degeneration with aging. This has been described for mice, rats, dogs, monkeys, and humans (Finch, 1993).
However, normal aging does not reliably produce a degeneration of the cholinergic innervation of the hippocampus. That is, aging does not necessarily cause death of cholinergic neurons, but it seems that the functioning of the cholinergic system is impaired during aging instead (Decker, 1987).
1.7.4. Serotonin
Serotonin (5-hydroxytryptamine, 5-HT) is predominantly an inhibitory neurotransmitter. Serotonergic fibers, originating from the raphe nuclei (Amaral and Cowan, 1980), spread all over the hippocampal formation. Serotonergic axons of the dorsal raphe nucleus are very fine and have small varicosities that do not make synaptic contacts (Fig. 1.4). Approximately 20% of the serotonergic fibers in the hippocampal formation make synaptic contact, mostly to GABAergic interneurons (Fig. 1.4). These fibers arise from the median raphe nucleus, and have large boutons that always make synapses.
The serotonergic system is known to modulate mood, emotion, sleep and appetite and thus is implicated in the control of numerous behavioral and physiological functions. Serotonin on its own seems to have no significant influence on learning and memory, however, the serotonergic system is shown to have strong interactions with the cholinergic system, also in the hippocampal formation (Steckler and Sahgal, 1995). The effects of aging on the serotonergic neurotransmission in the hippocampal formation have not been investigated extensively. Studies on serotonin content in the hippocampal formation of aging rodents either report a decrease (Luine et al., 1990), an increase (Van Luijtelaar et al., 1992) or no change (Miguez et al., 1999; Magnone et al., 2000; Stemmelin et al., 2000).
Studies on fiber densities during aging are rare and not comprehensive enough to make solid conclusions. Rodent studies indicate that serotonergic fiber densities decrease with advancing age in at least some regions of the hippocampal formation (Davidoff and Lolova, 1991; Van Luijtelaar et al., 1992; Nishimura et al., 1995).
1.7.5. Noradrenaline
Noradrenaline may have excitatory and inhibitory properties. Similar to the cholinergic and serotonergic innervation of the hippocampal formation, noradrenergic fibers are distributed throughout the entire hippocampal formation. The origin of the fine and varicose noradrenergic fibers, also probably in the rhesus monkey (Amaral and Cowan, 1980), is the locus coeruleus (Fig. 1.4). Noradrenergic varicosities of small sizes make synaptic contacts on GABAergic interneurons and on pyramidal cells. However, only a small part (15%) of the hippocampal noradrenergic varicosities form synapses, thus noradrenaline mainly acts by non-synaptic interactions.
The central functions of noradrenaline are regulation of alertness and of the wakefulness-sleep cycle, maintenance of attention, memory and learning, cerebral plasticity and neuroprotection. Studies on the content of noradrenaline in the aging hippocampal formation either demonstrate a reduction (Stemmelin et al., 2000;
Birthelmer et al., 2003) or no change (Luine et al., 1990; Miguez et al., 1999; Magnone et al., 2000). Although it was suggested that the aged primate brain is prone to degeneration of the locus coeruleus, stereological studies of the locus coeruleus of humans failed to demonstrate an aging-related neuron loss (Mouton et al., 1994; Ohm et al., 1997).
Nevertheless, as with the cholinergic system, a functional impairment may take place rather than loss of noradrenergic neurons.