Synaptic transmission in the striatum: from plasticity to neurodegeneration

Abstract

Striatal neurones receive myriad of synaptic inputs originating from different sources. Massive afferents from all areas of the cortex and the thalamus represent the most important source of excitatory amino acids, whereas the nigrostriatal pathway and intrinsic circuits provide the striatum with dopamine, acetylcholine, GABA, nitric oxide and adenosine. All these neurotransmitter systems interact each other and with voltage-dependent conductances to regulate the efficacy of the synaptic transmission within this nucleus. The integrative action exerted by striatal projection neurones on this converging information dictates the final output of the striatum to the other basal ganglia structures. Recent morphological, immunohistochemical and electrophysiological findings demonstrated that the striatum also contains different interneurones, whose role in physiological and pathological conditions represents an intriguing challenge in these years. The use of the in vitro brain slice preparation has allowed not only the detailed investigation of the direct pre- and postsynaptic electrophysiological actions of several neurotransmitters in striatal neurones, but also the understanding of their role in two different forms of corticostriatal synaptic plasticity, long-term depression and long-term potentiation. These long-lasting changes in the efficacy of excitatory transmission have been proposed to represent the cellular basis of some forms of motor learning and are altered in animal models of human basal ganglia disorders, such as Parkinson's disease. The striatum also expresses high sensitivity to hypoxic–aglycemic insults. During these pathological conditions, striatal synaptic transmission is altered depending on presynaptic inhibition of transmitter release and opposite membrane potential changes occur in projection neurones and in cholinergic interneurones. These ionic mechanisms might partially explain the selective neuronal vulnerability observed in the striatum during global ischemia and Huntington's disease.

Introduction

Over the last ten years the use of in vitro brain slice preparation to record single striatal neurones and the availability of more selective pharmacological compounds to isolate the function of various neurotransmitter receptors have allowed the understanding of the contribution of different transmitters in the generation and modulation of the electrical activity of striatal cells. The isolation of multiple ionic conductances in these neurones has provided information concerning the possible interaction between these ionic membrane mechanisms, which in most of the instances are voltage-dependent, and the ligand-operated mechanisms in single striatal neurones Akins et al., 1990, Calabresi et al., 1987, Cepeda et al., 1994, Howe and Surmeir, 1995. Moreover, the combined use of morphological, immunohistochemical and electrophysiological techniques gave the opportunity to identify not only the possible functional differences between spiny cells localised in various striatal compartments but also the synaptic and intrinsic characteristics of subpopulations of striatal interneurones Kawaguchi et al., 1995, Calabresi et al., 1998d. Fig. 1(A) demonstrates the heterogeneity of striatal neuronal population. Note that while most of the neurones are of small size, there is a minority of cells, which exhibit large somata. It is well known that most of striatal spiny neurones are GABAergic projecting cells. Fig. 1(B) shows a typical example of a striatal spiny neurone, which has been recorded by an intracellular microelectrode. During the intracellular recording the cell has been filled with biocytin for the subsequent morphological identification. Typical morphological features of striatal spiny neurones are:

• the small soma (10–18 μm); and

• the extensive dendritic tree, densely studded with spines Preston et al., 1979, Park et al., 1980, Wilson and Groves, 1980, Smith and Bolam, 1990, Wilson et al., 1990.

Interestingly, the morphological analysis, performed in a striatal slice from which a single neuronal element was recorded, showed, in some instances, that two or more spiny cells were stained, suggesting the existence of dye-coupling between striatal neurones. This observation could support the hypothesis that a non-synaptically mediated intercellular communication might occur in the striatum through gap junctions. It has been postulated that some neurotransmitters, such as dopamine (DA) might exert their physiological role by modulating the electrical coupling among sets of striatal neurones (Onn and Grace, 1994).

Physiological studies dealing with the electrical responses of striatal spiny neurones following the activation of various neurotransmitter receptors have suggested that these neuronal responses can be more complex than just depolarising (excitatory) or hyperpolarising (inhibitory) effects. In fact, as we will try to illustrate in this review, most of the neurotransmitters which are believed to play a key role in the integrative activity of the striatum do not cause prominent effects on the resting membrane properties of the recorded neurones. For example, high concentrations of muscarinic receptor agonists are required to cause membrane depolarisation of spiny cells while much lower concentrations are able to modulate synaptic transmission and to alter high voltage-activated (HVA) calcium (Ca²⁺) conductances (Dodt and Misgeld, 1986, Misgeld et al., 1986a; Misgeld et al., 1986b, Akaike et al., 1988, Akins et al., 1990, Sugita et al., 1991, Howe and Surmeir, 1995, Hsu et al., 1996, Calabresi et al., 1998a; Calabresi et al., 1998b). Similarly, activation of DA receptors, namely D1/D5 receptors, on these cells does not alter resting membrane potential (RMP) but regulates a voltage-dependent sodium (Na⁺) conductance which is involved in the control of the tonic firing discharge and of the characteristics of the excitatory postsynaptic potentials (EPSPs) (Calabresi et al., 1987, Surmeier et al., 1992; Surmeier et al., 1995, Schiffmann et al., 1995).

Interestingly, DA can also play another non-`classical' action within the striatum. In fact, this neurotransmitter exerts a permissive role in the long-term regulation of excitatory synaptic transmission. Accordingly, repetitive activation of corticostriatal fibres can induce two different forms of synaptic plasticity in the striatum, which are differentially regulated by D2 DA receptors. The discovery of a long-term depression (LTD) and of a long-term potentiation (LTP) following high frequency stimulation (HFS) of corticostriatal terminals (Calabresi et al., 1992a, Calabresi et al., 1992b, Lovinger et al., 1993, Walsh, 1993) has been regarded with particular interest since these forms of synaptic plasticity in other brain areas, such as the cortex, the hippocampus, and the cerebellum, have been considered as the cellular correlates of memory and learning Bliss and Lømo, 1973, Teyler and DiScenna, 1984, Artola and Singer, 1987, Ito, 1989, Kuba and Kumamoto, 1990, Bear and Malenka, 1994. Thus, a new field of interest is represented by the investigation of the role of various neurotransmitters in the induction-phase and in the maintenance-phase of striatal LTD and LTP. Behavioural evidence can also account for the growing interest in the mechanisms underlying striatal synaptic plasticity. In a recent review dealing with experimental lesion studies in monkeys, it has been raised the hypothesis that the striatum might have a critical role in memory formation (Parker and Gaffan, 1998). In fact, this structure might be involved in both reward-association memory and visual recognition memory. Interestingly, the striatum receives projections from different cortical areas. Although the projection from the motor cortex is well documented, the inputs from sensory, cingulate and association areas of the cortex are also largely represented Albin et al., 1989, Graybiel et al., 1994. None of these cortical areas have any apparent involvement in motor function. Thus, it is not surprising that many findings have revealed the involvement of the striatum in a large variety of non-motor functions (Calabresi et al., 1997a).

Clinical and experimental evidence suggests that short-term and long-term regulation of corticostriatal synaptic efficacy might be critical in some pathophysiological conditions. An altered corticostriatal synaptic activity has been implicated in Parkinson's disease and Huntington's disease (HD, Albin et al., 1989, Calabresi et al., 1996). Unfortunately, information on cellular mechanisms is not easily available from patients and animal models of these pathological conditions only partially mimic the behavioural characteristics of the human symptoms Beal et al., 1986, Kowall et al., 1987. Moreover, these animal models do not often express the temporal evolution of the disease, which is a critical feature of these neurodegenerative disorders Beal, 1992, Turski and Turski, 1993. Nevertheless, animal models have provided important data concerning the potential therapeutic efficacy of DAergic drugs in Parkinson's disease and the mechanisms underlying cell-type specific vulnerability in HD (Beal et al., 1986, Albin et al., 1989, Calabresi et al., 1993a; Calabresi et al., 1998c). In this review we will discuss electrophysiological data obtained at single neuronal level in the striatum from these models and we will try to correlate these data with the human pathology. Combined oxygen and glucose deprivation has provided an in vitro model of ischemia for eletrophysiological studies Haddad and Jiang, 1993, Martin et al., 1994, Calabresi et al., 1997d. These studies have shown that the striatum, as well as the hippocampus, is particularly vulnerable in this acute pathological condition. The high sensitivity of striatal spiny neurones to energy deprivation is expressed as a disruption of intrinsic membrane properties as well as an alteration of synaptic characteristics of the recorded cells (Xu, 1995). An issue that is particularly controversial at this regard is the potential role exerted by excitatory amino acids (EAAs) during ischemia and energy deprivation Novelli et al., 1988, Burke and Nadler, 1989, Martin et al., 1994, Buisson and Choi, 1995. The involvement of excitatory transmission in the striatum during this pathological condition will be discussed considering the various electrophysiological, biochemical and morphological observations on this topic.