D. James Surmeier
D. James Surmeier
Professor and Chairman
The research in our lab revolves around the question of how neuromodulators shape the excitability of basal ganglia neurons. The basal ganglia is a richly interconnected set of nuclei that regulate motor and cognitive behaviors. Disorders in basal ganglia function underlie a wide variety of psychomotor disorders including Parkinson's disease, dystonia, Huntington's disease, schizophrenia and Tourette's syndrome. In many of these diseases, the principal defect appears to involves an alteration in dopaminergic signaling. For example, the symptoms of Parkinson's disease are a consequence of the death of dopaminergic neurons that innervate one of the basal ganglia nuclei, the striatum.
One of our major goals has been to determine how dopamine modulates the excitability of striatal neurons. Unlike classical neurotransmitters, neuromodulators like dopamine influence neuronal activity by altering the properties of voltage-dependent and ligand-gated membrane channels. This is accomplished by G-protein coupled receptors that activate intracellular signaling cascades targeting ion channels. There are several obstacles to the characterization of these pathways and their cellular consequences. One is the tremendous molecular heterogeneity of participating proteins. Another is the difficulty in gaining a quantitative description of changes in channel behavior. To overcome these obstacles, we use a combination of electrophysiological, biochemical and molecular strategies. Patch-clamp techniques are used to quantitatively characterize the impact of receptor activation on ion channels. Biochemical techniques are used to identify the enzymes and signaling molecules linking receptor and channel. Molecular techniques, such as single cell mRNA amplification, are used to 'fingerprint' neurons subjected to electrophysiological and biochemical analyses. These single cell mRNA profiles allow us not only to determine the molecular identity of elements in a particular signaling cascade but also to determine the broader functional class to which a studied neuron belongs. The combination of these techniques has enabled us to make great strides in understanding the impact of neuromodulators, like dopamine, on basal ganglia function and, hopefully, will lead to new therapeutic strategies for basal ganglia disorders.
Figure: D2 receptor modulation of calcium currents in a strial medium spiney neuron depends on the release of intracellular Ca2+ via a PLC-dependent mechanism. A, Dialysis with BAPTA (20 mM) blocked the D2 modulation of tail currents but not peak currents. Voltage protocol is shown at the top. Inset, A box plot summarizes the modulations seen with BAPTA internals and matched controls. B, NPA (10 µM) reduced BAYK tail currents and increased intracellular Ca2+ levels in the same cells. Inset, The ratio of 510 nm fura-2 emission after excitation at 340 and 380 nm in the same neuron is shown. Measurements were taken while the cell was clamped at 80 mV and in the absence of external Ca2+. C, NPA failed to modulate slow tail currents in enkephalin-expressing neurons dialyzed with the PLC inhibitor U-73122. Inset, The recorded neuron expressed enkephalin but not substance P. D, Top, The gel shows RT-PCR amplicons for PLCbeta1-4 in pooled striatal mRNA. Bottom, The gel shows representative amplicons from four ENK-positive medium spiny neurons. Only PLCbeta1 mRNA was detected in ENK neurons.
Hernandez-Lopez S, Tkatch T, Perez-Garci E, Galarraga E, Bargas J, Hamm H, Surmeier DJ. (2000) D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLCbeta1-IP3-calcineurin-signaling cascade. J. Neurosci. 20:8987-8995.
Flores-Hernandez J, Hernandez S, Snyder GL, Yan Z, Fienberg AA, Moss SJ, Greengard P, Surmeier DJ. (2000) D(1) dopamine receptor activation reduces GABA(A) receptor currents in neostriatal neurons through a PKA/DARPP-32/PP1 signaling cascade. J. Neurophysiol. 83:2996-3004.
Tkatch T, Baranauskas G, Surmeier DJ. (2000) Kv4.2 mRNA abundance and A-type K(+) current amplitude are linearly related in basal ganglia and basal forebrain neurons. J. Neurosci. 20:579-588.
Kelz MB, Chen J, Carlezon WA Jr, Whisler K, Gilden L, Beckmann AM, Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T, Baranauskas G, Surmeier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ. (1999) Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine. Nature 401:272-276
Mermelstein PG, Foehring RC, Tkatch T, Song WJ, Baranauskas G, Surmeier DJ. (1999) Properties of Q-type calcium channels in neostriatal and cortical neurons are correlated with beta subunit expression.J. Neurosci.19:7268-7277.
Baranauskas G, Tkatch T, Surmeier DJ. (1999) Delayed rectifier currents in rat globus pallidus neurons are attributable to Kv2.1 and Kv3.1/3.2 K(+) channels. J. Neurosci. 19:6394-6404.