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. 2024 May 9;11(5):ENEURO.0010-24.2024.
doi: 10.1523/ENEURO.0010-24.2024. Print 2024 May.

Loss of Midbrain Dopamine Neurons Does Not Alter GABAergic Inhibition Mediated by Parvalbumin-Expressing Interneurons in Mouse Primary Motor Cortex

Suraj Cherian  1 , Gabriel Simms  1 , Liqiang Chen  1 , Hong-Yuan Chu  2
Affiliations

Loss of Midbrain Dopamine Neurons Does Not Alter GABAergic Inhibition Mediated by Parvalbumin-Expressing Interneurons in Mouse Primary Motor Cortex

Suraj Cherian et al. eNeuro. .

Abstract

The primary motor cortex (M1) integrates sensory and cognitive inputs to generate voluntary movement. Its functional impairments have been implicated in the pathophysiology of motor symptoms in Parkinson's disease (PD). Specifically, dopaminergic degeneration and basal ganglia dysfunction entrain M1 neurons into the abnormally synchronized bursting pattern of activity throughout the cortico-basal ganglia-thalamocortical network. However, how degeneration of the midbrain dopaminergic neurons affects the anatomy, microcircuit connectivity, and function of the M1 network remains poorly understood. The present study examined whether and how the loss of dopamine (DA) affects the morphology, cellular excitability, and synaptic physiology of Layer 5 parvalbumin-expressing (PV+) cells in the M1 of mice of both sexes. Here, we reported that loss of midbrain dopaminergic neurons does not alter the number, morphology, and physiology of Layer 5 PV+ cells in M1. Moreover, we demonstrated that the number of perisomatic PV+ puncta of M1 pyramidal neurons as well as their functional innervation of cortical pyramidal neurons were not altered following the loss of DA. Together, the present study documents an intact GABAergic inhibitory network formed by PV+ cells following the loss of midbrain dopaminergic neurons.

Keywords: 6-OHDA; Parkinson's disease; dopamine; motor cortex; optogenetics; parvalbumin.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Loss of midbrain DA neurons does not change the number of PV+ cells in M1. A, Representative confocal image of a sagittal section showing the distribution of tdTomato+ cells in the cerebral cortex of a PV-tdTomato mouse. B, C, Representative images showing the overlap between tdTomato fluorescence (B) and PV immunoreactivity (C) in two neurons in Layer 5 of M1. D–F, Representative confocal images showing PV+ cells in Layer 5 of M1 from the ipsilateral hemisphere of a control mouse (D) and both ipsilateral (E) and contralateral (F) hemispheres of a DA-depleted mouse. G, The summarized results showing no difference in the densities of L5 PV+ cells between controls and DD mice (ratio of ipsi-/contralateral M1 PV+ cells, controls = 1.02 [0.73, 1.08], n = 5 mice; DD = 1.16 [1.02, 1.25], n = 6 mice; p = 0.08, MWU, Table 1). ns, not significant.
Figure 2.
Figure 2.
Loss of DA neurons induces subtle changes in the morphology of PV+ cells in M1. A, B, Dendritic field of reconstructed L5 PV+ cells in the M1 of controls (A) and DD mice (B). C, Box plot showing no difference in the soma volume of PV+ cells between controls and DD mice (control = 1,022 [728, 1,838] µm3, DD = 835 [376, 1,177] µm3, p = 0.09, MWU, Table 1). D, Box plot showing no difference in the dendritic length of PV+ cells between controls and DD mice (control = 2,151 [1543, 2,856] µm, DD = 2,469 [1914, 2,786] µm, p = 0.27, MWU, Table 1). E, Box plot showing no difference in the number of primary dendrites of PV+ cells between controls and DD mice (control = 6 [5, 7.8], DD = 7 [6, 8], p = 0.3, MWU, Table 1). F, Box plot showing no difference in the number of branch points of PV+ cells between controls and DD mice (control = 13.5 [9, 15.75], DD = 13 [12, 15.5] µm, p > 0.9, MWU, Table 1). Morphology data were collected from and compared between 12 cells/3 mice for controls and 13 cells/3 mice for DD mice.
Figure 3.
Figure 3.
Loss of DA neurons does not alter the membrane properties of PV+ cells in M1. A, B, Images showing the recording location of PV+ cells from Layer 5 of M1 (A) guided by the tdTomato fluorescence (B). C, The K-means plot showing two separated clusters of PV+ cells in both controls and DD mice. D, The dendrogram showing two clusters of PV+ cells identified by using Ward's hierarchical clustering in both controls and DD mice. E, The summarized results showing differences in Cm of PV+ cells between clusters in both controls and DD mice (control/PV-CC = 40.1 [30.5, 52.4] pF, control/PV-IN = 24.1 [19.5, 28.2] pF, p < 0.0001; DD/PV-CC = 30.9 [27.1, 40.9] pF, DD/PV-IN = 22.7 [18.7, 28.3] pF, p = 0.003, Table 1). PV-CC cells in DD mice showed a decreased Cm relative to those in controls (p = 0.0082). F, The summarized results showing differences in Rin of PV+ cells between clusters in both controls and DD mice (control/PV-CC = 54.8 [44, 72.0] MΩ, control/PV-IN = 85.2 [75.3, 98.6] MΩ, p < 0.0001; DD/PV-CC = 56.2 [51.4, 70.1] MΩ, DD/PV-IN = 74.7 [68.5, 92.7] MΩ, p < 0.01, Table 1). There was no difference in Rin of PV-CC or PV-IN cells between controls and DD mice. G, H, Similar to F but for the rheobase (G, control/PV-CC = 415 [250, 488] pA, control/PV-IN = 151 [90, 228] pA, p < 0.0001; DD/PV-CC = 350 [278, 431] pA, DD/PV-IN = 150 [120, 200] pA, p < 0.0001, Table 1) and AP threshold (H, controls/PV-CC = −41.9 [−45.4, −39.9] mV, control/PV-IN = −47 [−49.1, −44.8] mV, p = 0.125; DD/PV-CC = −44.8 [−48.3, −41.3] mV, DD/PV-IN = −46.5 [−48.7, −44.3] mV, p = 0.2, Table 1). I, Representative traces of APs from PV-CC and PV-IN cells from controls (left) and DD mice (right). J, Similar to F but for the AP half-width (control /PV-CC = 0.16 [0.15, 0.18] ms, control/PV-IN = 0.21 [0.17, 0.23] ms, p = 0.0003; DD/PV-CC = 0.17 [0.15, 0.18] ms, DD/PV-IN = 0.20 [0.19, 0.23] ms, p < 0.003, Table 1). K, Similar to F but for the AP height (control/PV-CC = 76.3 [73.0, 79.2] mV, control/PV-IN = 89.1 [82.4, 94.2] mV, p < 0.0001; DD/PV-CC = 80.3 [73.3, 85.9] mV, DD/PV-IN = 88.3 [85.2, 92.1] mV, p < 0.0001, Table 1). Statistics were conducted based on 25 PV-CC and 21 PV-IN cells from seven controls, as well as 26 PV-CC and 31 PV-IN cells from eight DD mice using two-way ANOVA followed by Tukey's test.
Figure 4.
Figure 4.
Loss of DA does not change the intrinsic excitability of PV+ cells in L5 of M1. A, Representative trains of spikes evoked by different levels of somatic current injections into the PV-IN cells of controls and DD mice. B, F–I curve of L5 PV-INs in M1 from controls and DD mice. C, D, Similar to A and B but from PV-CC cells. Group difference p > 0.05 for curves in B and D, two-way ANOVA, Table 1.
Figure 5.
Figure 5.
Loss of DA does not alter GABAergic innervation of M1 pyramidal neurons. A, Representative confocal image showing PV+ perisomatic puncta (arrows) around eGFP-labeled PT neurons from controls and DD mice. B, Box plot showing no change in the number of perisomatic PV+ puncta around PT neurons between controls and DD mice (control = 36 [26, 50], n = 39 cells/4 mice; DD = 35 [26, 46], n = 45 cells/4 mice; p = 0.28, MWU, Table 1). C, D, Similar to A and B but for IT neurons (control = 33 [25, 39], n = 37 cells/4 mice; 6-OHDA = 33 [24, 39], n = 44 cells/4 mice; p = 0.8, MWU, Table 1). E, Representative images showing ChR2-eYFP–expressing terminals (left) were PV immunoreactive (middle and right) in the M1 of PV-ChR2 mice. * highlights PV+ cells with ChR2-eYFP expression on the membrane surface. # highlights putative cortical pyramidal neurons surrounded by PV+ perisomatic puncta. F–H, Representative spike traces of M1 pyramidal neurons of PV-ChR2 mice and their responses to long (blue bar) and short (blue dots) optogenetic stimulation (i.e., blue light) in regular ACSF and ACSF with GABAA receptor antagonist GABAzine (10 µM). I, Representative traces of optogenetically evoked IPSCs in PT neurons from controls and DD mice. Optogenetic stimulation intensity, 3.6 mW/mm2. K, Stimulation–amplitude curve of PV IPSCs in PT neurons from controls (n = 33 cells/4 mice) and DD mice (51 cells/8 mice). p > 0.05 for group difference, two-way ANOVA, Table 1. L, Box plot showing no changes in the paired-pulse ratio (PPR) of IPSCs in PT neurons between controls and DD mice (control = 0.7 [0.58, 0.79], n = 33 cells/4 mice; DD = 0.7 [0.53, 0.79], n = 51 cells/8 mice, p = 0.9, MWU, Table 1). J, M, N, Similar to I, K, and L but for M1 IT neurons (PPR in N, control = 0.65 [0.54, 0.75], n = 32 cells/4 mice, DD = 0.61 [0.47, 0.72], n = 33 cells/5 mice, p = 0.23, MWU, Table 1).
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References

    1. Aeed F, Cermak N, Schiller J, Schiller Y (2021) Intrinsic disruption of the M1 cortical network in a mouse Model of Parkinson’s disease. Mov Disord 36:1565–1577. 10.1002/mds.28538 - DOI - PubMed
    1. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366–375. 10.1016/0166-2236(89)90074-X - DOI - PubMed
    1. Baufreton J, Atherton JF, Surmeier DJ, Bevan MD (2005) Enhancement of excitatory synaptic integration by GABAergic inhibition in the subthalamic nucleus. J Neurosci 25:8505–8517. 10.1523/JNEUROSCI.1163-05.2005 - DOI - PMC - PubMed
    1. Brazhnik E, Cruz AV, Avila I, Wahba MI, Novikov N, Ilieva NM, McCoy AJ, Gerber C, Walters JR (2012) State-dependent spike and local field synchronization between motor cortex and substantia nigra in hemiparkinsonian rats. J Neurosci 32:7869–7880. 10.1523/JNEUROSCI.0943-12.2012 - DOI - PMC - PubMed
    1. Chen L, Daniels S, Dvorak R, Chu HY (2023) Reduced thalamic excitation to motor cortical pyramidal tract neurons in parkinsonism. Sci Adv 9:eadg3038. 10.1126/sciadv.adg3038 - DOI - PMC - PubMed

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