Wiring the Basal Ganglia: Direct and Indirect Pathway Glutamatergic Innervation in Mouse Striatum

As neurosurgeons and engineers attempt to understand the interactions of subcortical structures with applied electric fields, details of the underlying cellular circuitry become important. Studies of neuronal synaptic connections are difficult to perform and to interpret. But they are extremely important from both a comparative anatomy standpoint in understanding how our research animals are wired, and in beginning to elucidate normal brain function in man. Doig et al (J Neurosci. 2010 Nov 3;30(44):14610-14618) now present an in depth study of the major excitatory connections derived from thalamus and cortex on medium-sized spiny neurons (MSNs) in mouse striatum. In summary, these authors find similar proportions for the numbers of synapses formed via connections between cortex and thalamus on both direct and indirect pathway MSNs. A useful marker for MSNs of the direct basal ganglia pathway is the presence of the dopamine D1 receptor subtype, and for the indirect pathway it is the D2 receptor subtype. Similarly, the cortical or thalamic excitatory afferents to the striatum can be identified by their selective expression of the vesicular glutamate transporter, type 1 (VGluT1) by corticostriatal afferents and type 2 (VGluT2) by thalamostriatal afferents. In this study, Doig et al used transgenic mice that expressed enhanced green fluorescent protein (EGFP) under the D1 or D2 receptor promoters. They then performed double immunolabeling for the two different types of glutamate transporter (VGluT1 or VGluT2) along with labeling to reveal EGFP in whole brain sections from the transgenic mice. This allowed the authors to correlate the presynaptic origin of these striatal connections (cortical or thalamic) with the influenced basal ganglia circuitry (direct vs indirect). The primary results of this work include the fact that there were no differences in the structural characteristics of the individual synaptic terminals in terms of terminal size and vesicle distributions for either the VGluT1 (corticostriatal) or VGluT2 (thalamostriatal) synaptic connections. Additionally, D1 and D2 positive structures both received synaptic input from VGluT1- and VGluT2-positive terminals, with no statistical differences in synaptic connection numbers (Figure). The labeling data also demonstrated high levels of divergence with both cortical and thalamic axonal branches contacting both direct and indirect pathway MSNs. Convergence from different excitatory sources (cortical and thalamic) onto a given MSN was also inferred from the data.Figure: Reprinted with permission from the Journal of Neuroscience.Doig et al have found that the cortical and thalamic excitatory pathways into the striatum innervate MSNs (both the intermingled direct and indirect pathway cells) in similar numbers. This is despite the known differences in neurochemistry and subsequent connection locations of the direct and indirect pathways. The caveat for neurosurgeons or neuroengineers is that this data was obtained in mice, however it could provide a roadmap for performing similar immunolabeling studies in primate. These types of quantitative subcortical circuit analyses will doubtless become more important as we refine our neuromodulatory treatment of the movement disorders. Stan Anderson