Nicola B. Mercuri

LONG-TERM CHANGES OF CORTICOSTRIATAL SYNAPTIC TRANSMISSION: POSSIBLE IMPLICATION FOR MOTOR MEMORY

Intracellular and extracellular recordings from striatal neurons maintained in brain slices have shown that the activation of corticostriatal terminals produces excitatory postsynaptic potentials (EPSPs) mediated by the release of excitatory amino acids. Tetanic stimulation of cortical fibers induces long-term depression (LTD) of corticostriatal transmission. Membrane depolarization during the tetanus was required to produce LTD. LTD was not blocked by AVP indicating that the activation of NMDA receptors is not required for this event. LTD was blocked either by intracellular application of calcium (Ca2+)-chelators or by bath application of the Ca2+ channel blocker nifedipine suggesting that a rise in intracellular Ca2+ levels is necessary for the generation of striatal LTD. LTD was also blocked by inhibitors of Ca2+-dependent protein kinases. The role of metabotropic glutamate receptors (mGluRs) and of dopamine (DA) receptors in the formation of this form of synaptic plasticity was studied by utilizing different pharmacological and physiological approaches. When NMDA receptors were deinactivated by removing magnesium (Mg2+) from the external medium, the same tetanic stimulation which in control condition produced LTD, under this condition caused long-term potentiation (LTP) of synaptic transmission. LTP was fully blocked by NMDA-receptor antagonists. Our findings show that in the striatum it is possible to induce both LTD and LTP of excitatory synaptic transmission. These forms of synaptic plasticity may play a role in motor memory.

Basic Electrophysiology and Possible New Therapeutic Approaches to Movement Disorders

What the basal ganglia do, is it the on-going question? New models have reevaluated the input/output ratio of single structures as inserted in parallel, functional systems (Alexander and Crutcher, 1990). These models have reinforced the assumption that the basal ganglia are a key station for the execution of organized movements (DeLong, 1990; Goldman-Rakic and Selemon, 1990). At the molecular level, new families of receptors are explored. The cloning of glutamate metabotropic receptors is heading the surprising multiplicity of the neurobiology of excitatory transmission (Gasic, 1992). The definition of new subclasses of dopamine receptors is an invitation to reconsider the pharmacology of the amine (Surmeier et al., 1992). Radical changes, however, in the therapy of movement disorders have barely taken place, being the introduction of levo-dopa still a “cornerstone” of the therapy of the parkinsonian patient (Hornykiewicz, 1966). Whatever are the fundamental functions of the basal ganglia, a striking dichotomy risks to develop between basic research acquisition and the daily urgency of patient’s quality of life. In presenting our recent findings, we aim to highlight those aspects of mesencephalic, neostriatal and pallidal physiology whose clinical impact could be relevant.

Trace Amines Cause More than One Effect on Dopaminergic Neurons

Trace amines (TAs) are endogenous amines found in many organisms from plants, bacteria, insects and other invertebrates to mammals, including man. These compounds are detected at low concentrations in peripheral and brain tissues of vertebrates and are also ingested by a diet rich in chocolate, aged cheese and wine (Skerritt, et al., 2000). These amines include: tyramine (TYR), -phenylethylamine ( -PEA), tryptamine, (TRY) and octopamine (OCT; Fig. 1; Juorio, 1976). TAs are distributed heterogeneously throughout mammalian brain, in particular highest levels of TYR and -PEA are found in the nigrostriatal and mesolimbic regions, such as the caudate-putamen, olfactory tubercles and nucleus accumbens (Paterson, et al., 1990). It is likely that TAs are phylogenetically older than classical biogenic amines, dopamine (DA), norepinephrine (NE) and serotonin (5-HT), with whom they share structural proprieties and metabolic pathways (Paterson, et al., 1990), but their physiological roles and mechanisms of action in vertebrates remain unclear (Borowsky, et al., 2001; Bunzow, et al., 2001; Kim and von Zastrow, 2001; Premont, et al., 2001; Branchek and Blackburn, 2003). However, alterations in their amount are associated with various human disorders including schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), Parkinson disease (PD), addiction (Branchek and Blackburn, 2003). Moreover, brain levels of TAs are elevated during inhibition of the monoamine oxidase (MAO) enzyme (MAO-A and MAO-B) or in animals with selective deletion of MAO genes. TAs are stored in nerve terminals with classical biogenic amines and released together with them; however, they might not be stored in vesicles (Kosa, et al., 2000). Pharmacological studies have suggested that these compounds may function primarily as “endogenous amphetamines” or “false neurotransmitters” which increase catecholamine concentrations by interfering with the transport systems of the active biogenic amines.

New Insights Into mGluRs Function in the Substantia Nigra Pars Compacta

Metabotropic glutamate receptors (mGluRs) regulate many processes in the central nervous system (CNS), including synaptic plasticity, learning, memory, motor coordination, pain transmission and neurodegeneration (Linden et al., 1991; Nicoletti et al., 1996; Conn and Pin, 1997). They form a family of eight subtypes classified into three groups, I through III (Masu et al., 1991; Houamed et al., 1991; Nakanishi, 1992; Knopfel et al., 1995; Conn and Pin, 1997), which are implicated in different aspects of physiology and pathology of the CNS: group 1 (mGluRs land 5) are mainly localized on post-synaptic membranes and are coupled to intracellular calcium pools and to membrane ion channelsviaG-proteins, whereas group II and III are localized pre-synaptically and negatively coupled to adenylate cyclase (Pin and Duvoisin, 1992). The group I mGluRs generate slow EPSPs and calcium responses in cerebellar Purkinje neurons (Batchelor and Garthwaite, 1997) and hippocampal pyramidal neurons (Congar et al., 1997). Transient mGluR-mediated calcium increases can be elicited by stimulation of IP3sensitive (Murphy and Miller, 1989, Takechi et al., 1998) and/or ryanodine-sensitive (Berridge, 1998) receptors localized on intracellular calcium stores A family of proteins has been recently described, whose expression is driven by synaptic activity (Brackeman et al., 1997), as a physical link between mGluRs and either IP3—sensitive or ryanodinesensitive receptors, termed Homer protein (Brakeman et al., 1997, Tu et al., 1998) and this represents a novel mechanism in calcium signaling and might provide molecular insight into the synaptic function of Homer proteins.

Role of D1 and D2 Dopamine Receptors in the Mammalian Striatum: Electrophysiological Studies and Functional Implications

Pharmacological, biochemical, and anatomical studies have indicated that at least two receptors for dopamine (D1 and D2) are present in mammalian CNS (Creese et al., 1983; Stoof and Kebabian, 1984). D1 receptors are associated with the stimulation of adenylate cyclase, while D2 receptors mediate either the inhibition of adenylate cyclase or are unlinked with this enzyme. Although the pharmacological evidence in favor of this receptor heterogeneity is strong, the physiological and clinical implications of these receptor classifications are not fully clarified.