Gloria E. Meredith

‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease

Why dopamine-containing neurons of the brain’s substantia nigra pars compacta die in Parkinson’s disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Cav1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson’s disease. These mechanisms remain latent in adulthood, and blocking Cav1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking (‘rejuvenation’) protects these neurons in both in vitro and in vivo models of Parkinson’s disease, pointing to a new strategy that could slow or stop the progression of the disease.

Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson’s disease

We have detected granular and filamentous inclusions that are alpha-synuclein- and ubiquitin-immunoreactive in the cytoplasm of dopaminergic and cortical neurons of C57/black mice treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid. The immunoreactive aggregates only become evident several weeks after large-scale dopaminergic cell death and a downregulation of alpha-synuclein gene expression. Numerous lipofuscin granules accumulate alpha-synuclein in the nigral and limbic cortical neurons of treated mice. These data provide evidence that insoluble proteins, such as alpha-synuclein, build up as granular and filamentous inclusions in dopaminergic neurons that survive the initial toxic MPTP insult. They further suggest that defective protein degradation rather than altered gene expression underlies deposition of alpha-synuclein and that abundant lysosomal compartments are present to seal off the potentially toxic material.

Animal models of Parkinson’s disease progression

Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose etiology is not understood. This disease occurs both sporadically and through inheritance of single genes, although the familial types are rare. Over the past decade or so, experimental and clinical data suggest that PD could be a multifactorial, neurodegenerative disease that involves strong interactions between the environment and genetic predisposition. Our understanding of the pathophysiology and motor deficits of the disease relies heavily on fundamental research on animal models and the last few years have seen an explosion of toxin-, inflammation-induced and genetically manipulated models. The insight gained from the use of such models has strongly advanced our understanding of the progression and stages of the disease. The models have also aided the development of novel therapies to improve symptomatic management, and they are critical for the development of neuroprotective strategies. This review critically evaluates these in vivo models and the roles they play in mimicking the progression of PD.

Behavioral Models of Parkinson's Disease in Rodents: A New Look at an Old Problem

The circuitry important for voluntary movement is influenced by dopamine from the substantia nigra and regulated by the nigrostriatal system. The basal ganglia influence the pyramidal tract and other motor systems, such as the mesopontine nuclei and the rubrospinal tract. Although the neuroanatomical substrates underlying motor control are similar for humans and rodents, the behavioral repertoire mediated by those circuits is not. The principal aim of this review is to evaluate how injury to dopamine‐mediated pathways in rodents gives rise to motor dysfunction that mimics human Parkinsonism. We will examine the behavioral tests in common use with rodent models of Parkinsons disease and critically evaluate the appropriateness of each test for detecting motor impairment. We will show how tests of motor performance must be guided by a thorough understanding of the clinical symptoms accompanying the disease, the circuitry mediating dopamine deficits in rodents, and familiarity with the rodent behavioral repertoire. We will explain how investigations in rodents of skilled forepaw actions, including placing, grooming, or foot faults, have clear correlates in Parkinsons disease, and are, therefore, the most sensitive ways of detecting motor impairment following dopamine loss from the basal ganglia of rodents.

Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol.

Formidable challenges for Parkinsons disease (PD) research are to understand the processes underlying nigrostriatal degeneration and how to protect dopamine neurons. Fundamental research relies on good animal models that demonstrate the pathological hallmarks and motor deficits of PD. Using a chronic regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p) in mice, dopamine cell loss exceeds 60%, extracellular glutamate is elevated, cytoplasmic inclusions are formed and inflammation is chronic. Nevertheless, isradipine, an L-type calcium-channel blocker, attenuates the degeneration. These data support the validity of the MPTP/p model for unravelling the degenerative processes in PD and testing therapies that slow their progress.

The structural basis for mapping behavior onto the ventral striatum and its subdivisions

The striatum can be divided into dorsal (caudate-putamen) and ventral parts. In the ventral division, the nucleus accumbens, which subserves adaptive and goal-directed behaviors, is further subdivided into shell and core. Accumbal neurons show different types of experience-dependent plasticity: those in the core seem to discriminate the motivational value of conditioned stimuli, features that rely on the integration of information and enhanced synaptic plasticity at the many spines on these cells, whereas shell neurons seem to be involved with the release of predetermined behavior patterns in relation to unconditioned stimuli, and the behavioral consequences of repeated administration of addictive drugs. In the core, the principal neurons are medium sized and densely spiny, but in the medial shell, these same neurons are much smaller and their dendrites, significantly less spiny, suggesting that morphological differences could mediate unique neuroadaptations associated with each region. This review is focused on evaluating the structural differences in nucleus accumbens core and shell neurons and discusses how such different morphologies could underlie distinguishable behavioral processes.

Topographical organization of projections from the entorhinal cortex to the striatum of the rat

The efferent projections of the entorhinal cortex to the striatum were studied with retrograde (horseradish peroxidase wheat germ agglutinin) and anterograde (biocytin and biotinylated dextran amine) tracing methods. The bulk of the entorhinal cortical fibres were found to project to the nucleus accumbens in the ventral striatum, but the caudate putamen is only sparsely and diffusely innervated, rostrally, along its dorsal and medial borders. Fibres arising from neurons in the lateral entorhinal cortex project throughout the rostrocaudal extent of the nucleus accumbens but are most abundant in the core and lateral shell of that nucleus. The rostral neurons of the medial entorhinal cortex were found to project sparsely to the striatum, whereas caudal neurons provide a dense input to the rostral one-third of the nucleus accumbens, especially to the rostral pole, where they concentrate more in the core than in the shell. Contralateral entorhinal projections, which are very sparse, were found in the same parts of the nucleus accumbens and the caudate-putamen as the ipsilateral terminal fields. The present observations that entorhinal inputs to the nucleus accumbens are regionally aligned suggest that disruption of these connections could produce site-specific deficits with, presumably, specific behavioural consequences.

Immunocytochemical characterization of catecholaminergic neurons in the rat striatum following dopamine‐depleting lesions

It is possible either permanently or transiently to deplete the rat striatum of dopamine. Following such depletions, striatal neurons immunoreactive for tyrosine hydroxylase (TH), aromatic l‐amino acid decarboxylase (AADC) or dopamine appear. The presence of dopamine‐producing neurons in the striatum has relevance for the treatment of Parkinsons disease, but whether these catecholaminergic phenotypes all produce dopamine is unclear. In the present study we establish that after unilateral 6‐hydroxydopamine lesions or methamphetamine administration, striatal TH‐immunoreactive neurons differ in size, morphology and location from those that are immunopositive for AADC or dopamine. The TH‐positive cells which were localized either to ventral parts of the striatum or to the central and dorsal areas of the caudate‐putamen generally have the morphological features of projection neurons, whereas those containing AADC or dopamine were confined to subcallosal positions in the dorsal medial quadrant of the caudate‐putamen and resemble small, local‐circuit neurons. The fact that AADC‐immunoreactive neurons overlap in size, morphology and location with the cells that produce dopamine suggests strongly that this population is dopaminergic. However, the simultaneous appearance of neurons that contain the TH enzyme but clearly do not make dopamine raises questions about the functional role of these cells and the cellular mechanisms responsible for their induction following striatal dopamine loss.

Impaired glutamate homeostasis and programmed cell death in a chronic MPTP mouse model of Parkinson’s disease

The pathogenesis of Parkinsons disease is not fully understood, but there is evidence that excitotoxic mechanisms contribute to the pathology. However, data supporting a role for excitotoxicity in the pathophysiology of the disease are controversial and sparse. The goal of this study was to determine whether changes in glutamate signaling and uptake contribute to the demise of dopaminergic neurons in the substantia nigra. Mice were treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid or vehicle (probenecid or saline alone). Extracellular levels of glutamate in the substantia nigra were substantially increased, and there was an increase in the affinity, but no change in the velocity, of glutamate transport after MPTP/probenecid treatment compared to vehicle controls. In addition, the substantia nigra showed two types of programmed death, apoptosis (type I) and autophagic (type II) cell death. These data suggest that increased glutamate signaling could be an important mechanism for the death of dopaminergic neurons and trigger the induction of programmed cell death in the chronic MPTP/probenecid model.

Microcircuits in nucleus accumbens’ shell and core involved in cognition and reward

Nucleus accumbens subserves numerous adaptive and goal-directed behaviors. The anatomical substrates for such are the medium spiny projection neurons, at least four different subtypes of local circuit neurons, and inputs from limbic cortical centers and brainstem monoamines. In this review, we show how microcircuits in two parts of the nucleus—the core and caudomedial shell or septal pole— differ subtly in their connections yet permit quite different behaviors. We further show how small differences in synaptic wiring, especially in relation to the local circuit neurons, can facilitate or suppress behavioral activity. Finally, we consider some important organizational principles that underlie cognitive, emotional, and rewarding behaviors.