368 Dispatch

Basal ganglia: New therapeutic approaches to Parkinson’s diseaseAnn M. Graybiel

As the search for molecular therapies for basal gangliadisorders, such as Parkinson’s disease, accelerates,new neurobiological information is also leading torenewed interest in neurosurgical approaches.

Address: Department of Brain and Cognitive Sciences, MassachusettsInstitute of Technology, Building E25, Room 618, Cambridge,Massachusetts 02139, USA.

Current Biology 1996, Vol 6 No 4:368–371

© Current Biology Ltd ISSN 0960-9822

The motor symptoms of basal ganglia disorders fall at twoextremes. In Parkinson’s disease and related parkinsonianstates, patients have difficulty in initiating movements. InHuntington’s disease and related choreoathetotic disor-ders, patients make unwanted movements. Evidence haslong placed two brain structures at the center of researchon these disorders: the dopamine-synthesizing substantianigra of the midbrain, which degenerates in Parkinson’sdisease, and the striatum of the forebrain, which degener-ates in Huntington’s disease. How neurodegeneration inthese two nuclei could bring about such different symp-toms has so far not made much neurobiological sense. Thedopamine-containing cells of the substantia nigra innervatethe striatum, so it appears that loss of dopaminergic inner-vation of the striatum produces the hypokinetic disorder ofParkinson’s disease; and yet the loss of striatal cells them-selves produces hyperkinetic disorders such as Hunting-ton’s disease. New neurobiological clues to the functionalorganization of the basal ganglia are now helping with bothmolecular biological and more classical approaches totreating these debilitating neurological disorders.

The potential of the molecular approach is demonstratedby the recent cloning of the Huntington’s disease gene[1] and identification of proteins that interact with thegene’s product, Huntingtin [2]. These represent majorsteps towards the development of a gene-based therapyfor Huntington’s disease. But what about Parkinson’sdisease, which is not associated with a clear geneticdefect? The success of L-DOPA in relieving symptoms ofParkinson’s disease was a pioneering example of asuccessful molecular-replacement therapy in neurology;L-DOPA is the biosynthetic precursor of dopamine.L-DOPA-based therapies tend, however, to lose effec-tiveness with time, and L-DOPA itself can induce abnor-mal and debilitating motor side effects (dyskinesias).Even without a clear genetic basis for Parkinson’s disease,new molecular approaches to manipulating the dopaminesystem are being developed.

By targeted gene inactivation, ‘knockout’ mice have beengenerated that lack single dopamine receptor subtypes[3–7], or the dopamine transporter [8]. The receptormutants demonstrate clear receptor-specific effects ofdopamine on neurotransmission and behavior, and thetransport mutants show remarkable behavioral changes aswell. These mutant mice will be of great value in speed-ing the development of new pharmacological treatment ofdopamine-based disorders. They also bring surprisesabout the molecular events responsible for the effects ofaddictive drugs such as amphetamine and cocaine.

Zhou and Palmiter [9] have used an imaginative combinedknockout/transgene strategy to generate mutant mice thatspecifically lack dopamine in the substantia nigra. Theyfirst generated knockout mice lacking tyrosine hydroxy-lase, an enzyme involved in synthesis of catecholaminessuch as dopamine and noradrenaline. The knockout micedie as embryos, but could be rescued by a tyrosine hydrox-ylase transgene that conferred synthesis of noradrenaline,but not dopamine, in neurons of the noradrenergic locuscoeruleus. The rescued mice showed the classical signs ofdopamine deficiency, dying at about two weeks of age. Ifgiven L-DOPA therapy, however, the mice lived andshowed great improvement on all but the most complexmotor tasks. Even more selective targeting strategies,using cell- or region-specific promoter sequences, offergreat potential for devising new gene-based therapies.

A development in molecular biology that has clear thera-peutic potential for treating Parkinson’s disease is thecloning of genes encoding neurotrophins and growthfactors. For example, glial-derived neurotrophic factor(GDNF) has been reported to halt the progression ofdegeneration in the substantia nigra induced by theneurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine) [10] or by axotomy [11], and preliminary tests ofGDNF infusion to reduce symptoms in primate parkinson-ian models are reported as being promising [12]. Even thesignalling molecule Sonic hedgehog, known to have impor-tant roles in a number developmental contexts, may be animportant player — it can induce neurons of the developingmidbrain to differentiate with a dopaminergic phenotype invitro [13]. These results suggest new therapeutic strategiesin which molecules that promote the differentiation or sur-vival of dopaminergic neurons are delivered to appropriatetargets by using infusion techniques or transplantation.

At a time when molecular genetic techniques are advanc-ing so rapidly and seem so promising, it is ironic thatneurosurgery, a traditional and often last-hope approach to

basal ganglia disorders, is re-emerging as a major way oftreating Parkinson’s disease [14–22]. The renewed inter-est in neurosurgical treatments for Parkinson’s disease isbased on the use of new neurobiological information todetermine precise targets for the brain lesions. The centralidea prompting the neurosurgical effort is that theextremes of motor disability found in hypokinetic andhyperkinetic basal ganglia disorders reflect imbalancesbetween two major basal ganglia pathways: a ‘direct’pathway (or family of pathways) from the striatum tomotor executive regions, and an ‘indirect’ pathway thatmodulates the direct one (Fig. 1) [23–25].

Both the direct and the indirect pathways lead to parts ofthe globus pallidus and to the non-dopaminergic (reticular)part of the substantia nigra. The direct pathway leads on tothe thalamus and frontal cortex or, via the substantia nigra,to the brainstem. The neocortex can excite this directpathway by releasing an excitatory amino acid, such asglutamate, from corticostriatal terminals, and because twoinhibitory — g-amino-butyric acid (GABA)-releasing —synapses then follow in a row (Fig. 1), the circuit isthought to activate cortical and brainstem movementcenters. The indirect pathway is supposed to have exactlythe opposite effect, because it includes an excitatory linkin a small but pivotal nucleus, the subthalamic nucleus.The subthalamic nucleus turns on inhibition in the directpathway. This push-pull system, so current notions go,

works by enhancing movement through activity in thedirect path and diminishing it through activity in the indi-rect path ([23,24], but see [26]). This notion has shiftedthe therapeutic focus away from the dopaminergic sub-stantia nigra and striatum to the pallidum and subthalamicnucleus.

Neurosurgical lesions are being made — first in MPTP-treated parkinsonian monkeys [27] and now in patientswith Parkinson’s disease [14,16–18,21,22] — to increasemobility by decreasing tonic direct pathway inhibition ofthe thalamus. Localized high-frequency stimulation deliv-ered by portable stimulators is also being vigorouslypursued as a way of making reversible, ‘functional lesions’[15,19,20]. The targets for the lesions are the subthalamicnucleus, the thalamus and now (the preference of manygroups) the internal segment of the globus pallidus (Fig.1). Dramatic and immediate symptomatic relief can occurwith a posteroventral pallidal lesion, as originally docu-mented by Leksell [14] and Laitinen [16] and theircoworkers. Most patients remain on L-DOPA, however,and reports based on careful ongoing studies (for example[22]) do not make claims of complete reversal of symp-toms. Long-term follow-ups have not yet been possible. A key feature of the pallidotomy procedure appears to beto confine the lesion to the most strictly ‘motor’ (pos-teroventral) part of the pallidum and/or associated fiberbundles. This requires demanding collaborative efforts of

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Figure 1

Summary of basal ganglia circuits. Five keynuclei of the circuit are shown in pale green.Major inputs to the circuit lead to the striatumfrom the cerebral cortex, the amygdala andthe intralaminar thalamus (CM-Pf). Thestriatum (which degenerates in Huntington’sdisease) is the source of three key pathwaysthrough the basal ganglia: First, the directpathway (blue), which has two GABAergicinhibitory links in a row, so that activation ofthe striatum is thought to disinhibit (‘release’)the motor thalamus and subsequently thefrontal cortex, as well as midbrain structuressuch as the superior colliculus andpedunculopontine nucleus (PPN). Second,the indirect pathway (red), which is thought towork in opposition to the direct pathwaybecause of the added link through thesubthalamic nucleus (Sth N) which excitesdirect pathway inhibitory function. And third,the striatonigral pathway to the parscompacta of the substantia nigra (SNc),which forms a loop (yellow) with thedopamine-containing nigrostriatal pathwaythat degenerates in Parkinson’s disease. Thetwo segments of the pallidum are alsointerconnected (purple). For clarity, a numberof subcircuits have been omitted. Grey arrowspoint to sites of neurosurgical intervention by

lesions or stimulation in Parkinson’s diseasepatients; the arrow pointing to the globuspallidus (GPi) indicates the site ofposteroventral pallidotomy discussed in text.

Most growth factor/neurotrophin andtransplant strategies are directed toward thenigrostriatal system. SNr, non-dopaminergic(reticular) part of the substantia nigra.

Cerebral cortex

Frontalcortex

Allcortex

Amygdala

Superiorcolliculus

PPN

CM-Pf

Thalamus

GPiSNr

Sth NGPeSNc

Dopamine

Striatum

+

+

+

+

–

––

–

–

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neurosurgeons, neurologists and physiologists to identifythe critical target site with extracellular recordingmethods.

Following posteroventral pallidotomy, a striking normal-ization of metabolic activity in the premotor/supplemen-tary motor cortex has been demonstrated by positronemission tomography (PET) scans [18,28]. This findingstrongly supports the notion that the pallidal lesiondecreases inhibition of thalamo-cortical circuits. Ironi-cally, however, one of the great successes of the pos-teroventral pallidotomy procedure calls into questionsome of the notions on which the surgery is based.Opinion is growing that the procedure is strikingly effec-tive in reducing L-DOPA-induced dyskinesias (forexample [21,22]), and it is not at all clear how this couldfit with enabling movement in Parkinson’s patients.Another puzzle is how the symptomatic relief can be sogreat when the treatment does not, apparently, involvethe reticular part of the substantia nigra, which containsmany direct path neurons affecting movement (Fig. 1).Finally, there are questions about whether the pallidallesions have cognitive effects as well — and, if so, whatmechanisms might underlie such effects.

Molecular therapies based on this notion of direct andindirect pathways are also rapidly being developed. Gluta-mate receptors are reasonable targets for such efforts tocontrol interactions between the direct and indirect path-ways [29], as are receptors for peptides coexpressed withGABA in the direct and indirect pathways [25,30]. Interestis also shifting back to the nigrostriatal system, especiallyas studies of knockout mice clearly show that dopamineD1 and D2 receptors can selectively control the expressionof direct and indirect pathway neuropeptides. D1 receptormutants have sharply diminished basal ganglia expressionof dynorphin [3] and substance P [3,4], the neuropeptidescoexpressed with GABA in the direct pathway, whereasD2 receptor mutants show loss of basal ganglia expressionof enkephalin, the neuropeptide coexpressed with GABAin the indirect pathway [7]. These contrasting effectssuggest that dopamine, acting at D1 and D2 receptors, canselectively affect the functioning of the direct and indirectpathways.

Perhaps the most optimistic view to take is that, whilegene- and growth-factor-based therapies are beingdevised to prevent neurodegeneration, strategies aimed atsymptomatic relief of Parkinson’s disease and other basalganglia disorders can profit from innovative combinationsof molecular biology and neurosurgery. There is, more-over, a real possibility that, as more is learned about theneurobiology of the basal ganglia, these strategies can beapplied to conditions involving, not only the motor symp-toms of basal ganglia dysfunction, but the cognitive andaffective symptoms as well.

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