Cellular Biology of the Basal Ganglia & Motor Disorders

Dr. Soghomonian’s research is focused on the functional and molecular neuroanatomy of the basal ganglia and the pathophysiology of Parkinson’s disease and l-DOPA-induced dyskinesia.

Current research:

1-Pathophysiology of Parkinson’s disease and l-DOPA-induced dyskinesia in a rodent model of the disease
2-Modulation of GABA-mediated signaling by dopamine receptors
3-Cellular/molecular abnormalities in post-mortem brains from patients with Parkinson’s disease

Dopamine and the basal ganglia

Parkinson’s disease is a neurodegenerative disease characterized by a loss of dopamine neurons in the brain. Motor abnormalities observed in Parkinson’s disease are due to abnormal cell signaling in brain regions such as the basal ganglia. The most common therapeutic intervention in Parkinson’ disease consists in administering orally the precursor of dopamine, L-dopa. However, long-term exposure to l-DOPA results in severe secondary effects such as dyskinesia, which seriously alter the therapeutic efficacy of l-DOPA. One objective of the laboratory is to understand how l-DOPA or agonists of dopamine receptors alter cell signaling in a rodent experimental model of Parkinson’s disease.

GABA-mediated signaling

GABA is a major inhibitory neurotransmitter in the mammalian brain. Another focus of the laboratory is to study the mechanisms involved in the regulation of GABA-mediated signaling by dopamine receptors in the normal brain and in models of Parkinson’s disease.

Publications

The lab publishes in various neuroscience journals. The following list presents some of the most recent publications.

Yamamoto N, Soghomonian JJ.Time-course of SKF-81297-induced increase in glutamic acid decarboxylase 65 and 67 mRNA levels in striatonigral neurons and decrease in GABA(A) receptor alpha1 subunit mRNA levels in the substantia nigra, pars reticulata, in adult rats with a unilateral 6-hydroxydopamine lesion. Neuroscience. 2008 Jun 26;154(3):1088-99. Epub 2008 Apr 16. PMID: 18495353 [PubMed - indexed for MEDLINE]

Yip J, Soghomonian JJ, Blatt GJ. Increased GAD67 mRNA expression in cerebellar interneurons in autism: implications for Purkinje cell dysfunction. J Neurosci Res. 2008 Feb 15;86(3):525-30. PMID: 17918742 [PubMed - indexed for MEDLINE]

Hatzipetros T, Raudensky JG, Soghomonian JJ, Yamamoto BK. Haloperidol treatment after high-dose methamphetamine administration is excitotoxic to GABA cells in the substantia nigra pars reticulata. J Neurosci. 2007 May 30;27(22):5895-902. PMID: 17537960 [PubMed - indexed for MEDLINE]

Yip J, Soghomonian JJ, Blatt GJ. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol. 2007 May;113(5):559-68. Epub 2007 Jan 18. PMID: 17235515 [PubMed - indexed for MEDLINE]

Wang H, Katz J, Dagostino P, Soghomonian JJ. Unilateral 6-hydroxydopamine lesion of dopamine neurons and subchronic L-DOPA administration in the adult rat alters the expression of the vesicular GABA transporter in different subsets of striatal neurons and in the substantia nigra, pars reticulata. Neuroscience. 2007 Mar 16;145(2):727-37. Epub 2007 Jan 9. PMID: 17218060 [PubMed - indexed for MEDLINE]

Yamamoto N, Pierce RC, Soghomonian JJ. Subchronic administration of L-DOPA to adult rats with a unilateral 6-hydroxydopamine lesion of dopamine neurons results in a sensitization of enhanced GABA release in the substantia nigra, pars reticulata. Brain Res. 2006 Dec 6;1123(1):196-200. Epub 2006 Oct 9. PMID: 17027936 [PubMed - indexed for MEDLINE]

Soghomonian JJ. L-DOPA-induced dyskinesia in adult rats with a unilateral 6-OHDA lesion of dopamine neurons is paralleled by increased c-fos gene expression in the subthalamic nucleus. Eur J Neurosci. 2006 May;23(9):2395-403. Erratum in: Eur J Neurosci. 2006 Sep;24(5):1505. PMID: 16706847 [PubMed - indexed for MEDLINE]

Katz J, Nielsen KM, Soghomonian JJ. Comparative effects of acute or chronic administration of levodopa to 6-hydroxydopamine-lesioned rats on the expression of glutamic acid decarboxylase in the neostriatum and GABAA receptors subunits in the substantia nigra, pars reticulata. Neuroscience. 2005;132(3):833-42. PMID: 15837143 [PubMed - indexed for MEDLINE]

Nielsen KM, Soghomonian JJ. Normalization of glutamate decarboxylase gene expression in the entopeduncular nucleus of rats with a unilateral 6-hydroxydopamine lesion correlates with increased GABAergic input following intermittent but not continuous levodopa. Neuroscience. 2004;123(1):31-42.

Nielsen KM, Soghomonian JJ. Dual effects of intermittent or continuous L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-OHDA lesion. Synapse. 2003 Sep 15;49(4):246-60.

Soghomonian, J.-J. and Martin, D.L., Two isoforms of glutamate decarboxylase: why? Trends in Pharmacological Sciences, 19 (1998) 500-505.

Soghomonian, J.-J. and Laprade, N., Glutamate decarboxylase (GAD67 and GAD65) gene expression is increased in a sub-population of neurons in the putamen of parkinsonian monkeys, Synapse, 27 (1997) 122-132

Laprade, N., Radja, F., Reader, T. and Soghomonian, J.-J., Dopamine receptor agonists regulate levels of the serotonin 5-HT2A receptor and its mRNA in a subpopulation of striatal neurons, Journal of Neuroscience, 16 (1996) 3727-3736.

Laprade, N. and Soghomonian, J.-J., Differential regulation of mRNA levels encoding for the two isoforms of glutamate decarboxylase (GAD65 and GAD67) by dopamine receptors in the rat striatum. Mol. Brain Res., 34 (1995) 65-74.

Methodology

Experimental models of Parkinson’s disease: Dopamine neurons in the substantia nigra, pars compacta, are lesioned following the stereotaxic injection of the neurotoxin 6-hydroxydopamine in anesthetized rats. Fresh-frozen brain sections are cut on a cryostat and processed for in situ hybridization histochemistry or immunohistochemistry.

Behavioral observations of motor activity are performed on adult rodent experimental models of Parkinson’s disease in observation chambers.

Immunohistochemistry or immunofluorescence is used on fresh-frozen tissue sections with antibodies directed against specific neurotransmitters or their receptors. This technique is used to study the distribution and expression of molecules involved in cell signaling in the basal ganglia.

In situ hybridization histochemistry is used on fresh-frozen tissue sections using riboprobes or oligonucleotide probes to study the distribution and expression of genes involved in cell metabolism and cell signaling.

Light microscopy is used to examine the distribution of immunostaining or mRNAs on tissue sections processed for immunohistochemistry or in situ hybridization histochemistry, respectively.

Quantitative image analysis of immunostaining is performed by computerized densitometry. Measurements of mRNA levels are performed at the single cell level on radioautographs by counting silver grains with a computerized image analysis system.

Microdialysis is used to assess changes in GABA levels in various regions of the basal ganglia induced by agonists of dopamine receptors in a rodent model of Parkinson’s disease. Separation of GABA is performed by HPLC followed by electrochemical detection of GABA derivative.

People

Jean-Jacques Soghomonian, Ph.D.
Dr. Soghomonian is the director of the laboratory. His research is focused on the functional neuroanatomy of the basal ganglia.

Amelie Lanoue is a graduate student in the laboratory. She is working on some aspects of GABA-mediated signaling in the cerebral cortex of a rodent model of Parkinson’s disease.

Natalia Lotz is a graduate student in the laboratory. She is working on the binding properties of GABA receptors in the subthalamic nucleus of a rodent model of Parkinson’s disease.