Antonio Pisani

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.

Recurrent Cerebral Venous Thrombosis in a 24-Year-Old Puerperal Woman

To the Editor: We read with interest the recent short communication by John N. Fink and colleagues1 on mastoid changes in patients with lateral venous sinus thrombosis (LST). Their observations are very interesting. Twenty-three LST were identified in 20 patients. Mastoid abnormalities were detected ipsilateral to 9 of the 23 thrombosed lateral sinuses. Only one patient showed signs of infection, but a diagnosis of mastoiditis seemed unlikely. This study is the first to suggest a new etiopathogenetic hypothesis for mastoid abnormalities in patients with LST. We support the authors’ view that in absence of clinical evidence of infection, treatment should be directed at the underlying cerebral venous sinus thrombosis. With reference to the above-mentioned study, we would like to report the case of a 24-year-old puerperal woman hospitalized and diagnosed with epileptic seizure. Prior to hospitalization, she experienced diffuse headache, right earache, nausea, vomiting, and mild left hemiparesis. At least 2 …

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.

Cholinergic Interneuron and Parkinsonism

Recent advances in our knowledge of striatal function revealed a previously unexpected role for striatal cholinergic interneurons. The recognition that interneurons are essential in synaptic plasticity and motor learning represents a significant progress in deciphering how the striatum processes cortical inputs, and why pathological circumstances cause motor dysfunction. Loss of the reciprocal modulation between dopaminergic inputs and the intrinsic cholinergic innervation within the striatum represents a suitable explanation for the efficacy of anticholinergic drugs both in Parkinson’s disease and in dystonia. These advances provide exciting indications to the underlying circuit alterations. In this chapter, we discuss the experimental and clinical evidence in attempt to clarify how alterations in striatal cholinergic signalling may contribute to motor dysfunction and ultimately to identify novel therapeutic strategies to fine-tune cholinergic signalling in basal ganglia disorders.

Glutamate Transmission in the Pathogenesis of Parkinson’s Disease

Parkinson’s disease (PO), a progressive neurodegenerative disorder, is a common cause of disability. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. The current pathophysiological concept of PD postulates a multifactorial origin, where alterations in neurotransmitter content are combined with genetic and environmental factors. With nigrostriatal dopamine depletion, a complex set of changes occurs in the functional anatomy of the basal ganglia circuitry. As a result, the firing pattern of certain glutamatergic pathways has been shown to change significantly, and to play a central role in the pathogenesis of parkinsonian symptoms. Advances in genetics have led to the discovery of gene mutations underlying some forms of PD. The mutated genes encode proteins of unknown function, such as alpha-synuclein and parkin. Moreover, compelling evidence supports the involvement of mitochondrial metabolism failure as an essential cofactor in the pathogenesis of PD. Interestingly, some environmental toxins are thought to be able to act as mitochondrial toxins. The comprehension of the pathways leading to PD requires an intense effort in order to identify and establish a plausible connection between genetic causes, altered neurotransmission and metabolic impairment.

Dopamine-Dependent Long-Term Potentiation Induced by 3-Nitropropionic Acid in Striatal Medium Spiny Neurons

The classical clinical symptoms of Huntington’s disease (HD) include abnormal involuntary movements (chorea) and cognitive impairment. This genetically determined disorder selectively involves degeneration of striatal spiny neurons while sparing striatal large cholinergic interneurons.1 HD is caused by an expansion of CAG repeats near the 5′ end of the IT15 gene. IT15 encodes an ubiquitously expressed protein called huntingtin. Moreover, a remarkable decrease in the activity of mitochondrial complex II (succinate dehydrogenase, SD) has been found in brains of HD patients.2 Indeed, the link between bioenergetic defects and excitotoxic mechanisms, two pathological events which seems to play a major role in HD3,4 to the mutated huntingtin, remains unknown. The corticostriatal projection represents one of the major glutamatergic pathways in the brain and an abnormal release of glutamate from this pathway seems to play a pathogenic role in HD. The complex II inhibitors 3-nitropropionic acid (3-NP) and methylmalonic acid (MMA) mimic the pathology of HD.5,6 Thus, enhanced glutamatergic transmission may trigger neurodegeneration in neurons, the energy metabolism of which is compromised due to impaired SD activity. We studied the electrophysiological effects of the pharmacological blockade of SD by either 3-NP or MMA on glutamatergic excitatory postsynaptic potentials (EPSPs), in order to investigate the link between metabolism impairment and glutamatergic transmission both in striatal spiny neurons and cholinergic interneurons. The t-LTP might play a key role in the regional and cell-type specific neuronal death observed in HD.