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This article gives a short historical account of the events and circumstances that led to the discovery of the occurrence of dopamine (DA) in the brain and its deficiency in Parkinson’s disease (PD). Some important consequences, for both the basic science and the patient, of the work on DA in the PD brain are also highlighted.

Early physiological studies emphasized changes in the discharge rate of basal ganglia in the pathophysiology of Parkinson’s disease (PD), whereas recent studies stressed the role of the abnormal oscillatory activity and neuronal synchronization of pallidal cells. However, human observations cast doubt on the synchronization hypothesis since increased synchronization may be an epi-phenomenon of the tremor or of independent oscillators with similar frequency. Here, we show that modern actor/critic models of the basal ganglia predict the emergence of synchronized activity in PD and that significant non-oscillatory and oscillatory correlations are found in MPTP primates. We conclude that the normal fluctuation of basal ganglia dopamine levels combined with local cortico-striatal learning rules lead to noncorrelated activity in the pallidum. Dopamine depletion, as in PD, results in correlated pallidal activity, and reduced information capacity. We therefore suggest that future deep brain stimulation (DBS) algorithms may be improved by desynchronizing pallidal activity.

In the traditional model of the pathophysiology of parkinsonism, parkinsonian motor signs are viewed as the result of changes in discharge rates in the basal ganglia. However, not all experimental findings can be explained by rate changes alone, and changes in discharge patterns in these nuclei are increasingly emphasized as pathophysiologically important, including changes in burst discharges, in synchrony, and in oscillatory activity. This brief review highlights the pathophysiologic relevance of these rate and pattern changes in the pathophysiology of parkinsonism.

Recordings in humans as a result of functional neurosurgery have revealed a tendency for basal ganglia neurons to oscillate and synchronise their activity, giving rise to a rhythmic population activity, manifest as oscillatory local field potentials. The most important activity is synchronised oscillation in the beta band (13–30 Hz), which has been picked up at various sites within the basal ganglia-cortical loop in PD. Dopaminergic medication and movement suppress this activity, with the timing and degree of suppression closely correlating with behavioural performance. Accordingly synchronisation in the beta band has been hypothesised to be essentially antikinetic in nature and pathophysiologically relevant to bradykinesia.

Objectives: To determine if novel methods establishing patterns in EEG-EMG coupling can infer subcortical influences on the motor cortex, and the relationship between these subcortical rhythms and bradykinesia. Background: Previous work has suggested that bradykinesia may be a result of inappropriate oscillatory drive to the muscles. Typically, the signal processing method of coherence is used to infer coupling between a single channel of EEG and a single channel of rectified EMG, which demonstrates 2 peaks during sustained contraction: one, ∼10 Hz, which is pathologically increased in PD, and a ∼30 Hz peak which is decreased in PD, and influenced by pharmacological manipulation of GABAA receptors in normal subjects. Materials and methods: We employed a novel multiperiodic squeezing paradigm which also required simultaneous movements. Seven PD subjects (on and off L-Dopa) and five normal subjects were recruited. Extent of bradykinesia was inferred by reduced relative performance of the higher frequencies of the squeezing paradigm and UPDRS scores. We employed Independent Component Analysis (ICA) and Empirical Mode Decomposition (EMD) to determine EEG/EMG coupling. Results: Corticomuscular coupling was detected during the continually changing force levels. Different components included those over the primary motor cortex (ipsilaterally and contralaterally) and over the midline. Subjects with greater bradykinesia had a tendency towards increased ∼10 Hz coupling and reduced ∼30 Hz coupling that was erratically reversed with L-dopa. Conclusions: These results suggest that lower ∼10 Hz peak may represent pathological oscillations within the basal ganglia which may be a contributing factor to bradykinesia in PD.

Glial cell line-derived neurotrophic factor (GDNF) has been known for many years to protect and restore dopamine neurons of the substantia nigra (SN) in lesion models of parkinsonism, but much less has been known of its normal physiologic role. We have found that GDNF injected into the striatum postnatally suppresses naturally-occurring cell death in SN dopamine neurons, and neutralizing antibodies augments it. Neutralizing antibodies augment cell death during the first phase, which occurs during the first postnatal week, but not during the second phase in the second week. To further explore the possible neurotrophic role of GDNF, we created double transgenic mice which overex-press GDNF exclusively in the target regions of mesencephalic neurons, particularly the striatum. As anticipated for a limiting, target-derived factor, this resulted in an increased surviving number of SN dopamine neurons after the first phase of cell death. However, this increase did not persist into adulthood. We conclude that GDNF is the leading candidate for a target-derived neurotrophic factor for SNdopamine neurons during the first phase of cell death, but that other factors must play an essential role in later development.

The engrailed genes belong to a large family of homeobox transcription factors. They are found throughout the animal kingdom, are highly conserved in the DNA binding domain and have been investigated for more than half a century. In the murine genome, two engrailed genes exist, called Engrailed-1 and Engrailed-2 . Here, we summarize the properties of the engrailed genes and their functions, such as conserved structures, cellular localisation, secretion and internalisation, transcription factor activity, potential target genes and review their role in the development of mesencephalic dopaminergic neurons. During early development, they take part in the regionalization event, which specifies the neuroepithelium that provides the precursor cells of the mesencephalic dopaminergic neurons with the necessary signals for their induction. Later in the post-mitotic neurons, the two transcription factors participate in their specification and are cell-autonomously required for their survival.

Dopamine belongs to the most intensively studied neurotransmitters of the brain, because of its implications in psychiatric and neurological disorders. Although, clinical relevance of midbrain dopaminergic (mDA) neurons is well recognized and dopaminergic dysfunction may have a genetic component, the genetic cascades underlying developmental processes are still largely unknown. With the advances in molecular biology, mDA neurons and their involvement in psychiatric and neurological disorders are now subject of studies that aim to delineate the fundamental neurobiology of these neurons. These studies are concerned with developmental processes, cell-specific gene expression and regulation, molecular pharmacology, and genetic association of dopamine-related genes and mDAassociated disorders. Several transcription factors implicated in the post-mitotic mDA development, including Nurr1, Lmx1b, Pitx3, and En1=En2 have contributed to the understanding of how mDA neurons are generated in vivo. Furthermore, these studies provide insights into new strategies for future therapies of Parkinson’s Disease (PD) using stem cells for engineering DA neurons in vitro. Here, we will discuss the role of Pitx3 in molecular mechanisms involved in the regional specification, neuronal specification and differentiation of mDA neurons.