The optogenetic, electrophysiological, pharmacological, and CRISPR-mediated genetic studies demonstrated that impaired α5-GABAA receptor-mediated inhibition and excessive activation of NMDA receptors of M1 pyramidal neurons are key microcircu it mechanisms underlying cortical circuit remodeling during progressive striatal dopamine loss.
Abstract
Dysfunction of the primary motor cortex (M1) has long been implicated in the pathophysiology of Parkinson’s disease (PD), mostly as a link by which abnormal basal ganglia and thalamic activities are translated into motor symptoms. However, emerging evidence suggests that M1 neurons also exhibit maladaptive changes in advanced parkinsonism. Here, using a progressive mouse model of nigrostriatal neurodegeneration (i.e., the MitoPark mice, MP), we found that M1 neurons develop age- and striatal dopamine-dependent synaptic and cellular adaptations as parkinsonism progresses. The optogenetic, electrophysiological, pharmacological, and CRISPR-mediated genetic studies demonstrated that impaired α5-GABAA receptor-mediated inhibition and excessive activation of NMDA receptors of M1 pyramidal neurons are key microcircu it mechanisms underlying cortical circuit remodeling during progressive striatal dopamine (DA) loss. Furthermore, we found that treatment with L-DOPA at early or late stages of parkinsonism can prevent or rescue, respectively, the synaptic and cellular adaptations in M1. Together, the present study demonstrates the time course and the underlying molecular and microcircuit mechanisms of cortical network dysfunction during the development of parkinsonism.
Parkinson’s disease (PD) is characterized by progressive dopaminergic degeneration and maladaptive motor cortical plasticity. However, the cellular pathways underlying cortical surface activity in the primary motor cortex (M1) remain unclear, despite serving as a potential target for electrotherapy. We investigated the excitatory–inhibitory (E-I) balance and synaptic plasticity of superficial M1 circuits in a unilateral 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Using extracellular local field potential and whole-cell patch recordings from the contralateral and ipsilateral M1 hemispheres of hemi-parkinsonian rats, we observed a significantly elevated field excitatory postsynaptic potential (fEPSP) input–output function but unchanged intrinsic neuronal excitability in the M1 superficial layer. An altered relative contribution between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated transmission was reflected by a significantly increased AMPA/NMDA ratio. Markedly reduced inhibitory synaptic tone was also evidenced by the decreased amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), supporting an E-I imbalance favoring excitation in PD. Furthermore, group I metabotropic glutamate receptor (mGluR1/5)-dependent long-term depression (LTD) was abolished in the ipsilateral PD hemisphere, whereas NMDAR-dependent LTD remained intact. In summary, dopamine depletion appears to enhance network excitation and disrupt mGluR1/5-mediated control of M1 surface circuitry. Our findings identify altered cortical surface mGluR-dependent plasticity in the hemi-parkinsonian model; however, the relationship between these electrophysiological alterations and individual motor outcomes remains to be determined.
Hongseong Shin, Yoon Ji Kwon, Hyunjung Hwang et al.· International Journal of Mol...· 0 citations
The main motor symptoms of Parkinson's disease (PD) emerge following dopamine depletion in the dorsal striatum and are associated with structural and functional adaptations of striatal medium spiny neurons (MSN). Although the indirect pathway MSN (iMSN) selectively expresses dopamine D2 receptors (D2R), the contribution of D2R signaling to these adaptations remains incompletely understood. Here, we examined neuronal morphology, dendritic spine density, corticostriatal transmission, and intrinsic excitability in direct pathway MSN (dMSN) and iMSN from constitutive D2R knockout mice, with or without chronic nigrostriatal lesions induced by 6-hydroxydopamine. D2R ablation reduced dendritic length and complexity in both MSN subtypes, although the effects were markedly greater in iMSN. In iMSN, D2R ablation also reduced spine density and increased intrinsic excitability, reproducing well known effects of nigrostriatal lesions and largely occluding additional effects of dopamine denervation. In contrast, D2R ablation produced only modest changes in dMSN spine density and excitability and did not prevent the additional spine loss and hyperexcitability induced by 6-OHDA lesions. Basal corticostriatal transmission remained largely preserved after D2R ablation in either MSN subtype, except for a slower excitatory postsynaptic current decay in iMSN, which was not enhanced further by the dopamine depleting lesion. Remarkably, nigrostriatal lesions continued to depress corticostriatal excitatory postsynaptic currents in D2R-deficient mice, indicating that this synaptic adaptation does not require D2R signaling. Together, these findings identify D2R signaling as a major determinant of iMSN structural and intrinsic physiological integrity and demonstrate that global loss of D2R function reproduces many of the adaptations induced by dopamine depletion. More broadly, they indicate that dopamine depletion drives distinct forms of plasticity through separable D2R dependent and independent mechanisms, with depression of corticostriatal synaptic currents in iMSN arising independently of D2R signaling.
Samuel Alberquilla, Carlos Salas Prieto, Paula Merino Serrais et al.· Neurobiology of Disease· 0 citations
Summary Background Beta-band (13–30 Hz) oscillations in the cortico-basal ganglia-thalamic (CBT) network strongly correlate with motor deficits in Parkinson’s disease (PD), yet their synaptic origins remain unclear. Given that dopamine (DA) loss is necessary but not sufficient to produce sustained beta rhythms, we hypothesised that corticostriatal glutamatergic overdrive may function as a significant non-dopaminergic amplifier of pathological synchrony. Methods Using an integrated experimental-computational approach, we combined 6-hydroxydopamine (6-OHDA) male rat models, ex vivo striatal patch-clamp recordings, chemogenetic modulation of corticostriatal projection, and multiscale computational network modelling to examine beta oscillation dynamics in the CBT network. Findings Early DA denervation caused akinesia without beta elevation, while advanced degeneration triggered robust high-beta (25–40 Hz) oscillations and increased corticostriatal coherence. Ex vivo, medium spiny neurons (MSNs) exhibited heightened presynaptic glutamate release correlated with beta power. Computational modelling showed that excessive corticostriatal input under DA depletion increased MSN synchrony, disrupted striatal decorrelation, and was associated with the emergence of pathological beta rhythms, effects reversed by reducing glutamatergic input. In vivo chemogenetic silencing of corticostriatal projections suppressed beta synchrony and improved motor performance in 6-OHDA rats, whereas activation in DA-intact rats had no effect. Notably, striatal NMDA, not AMPA, receptor blockade reduced beta oscillations and motor deficits. Network simulations implicated the subthalamic → motor cortex feedback loop in the maintenance of this pathological beta state. Interpretation Corticostriatal glutamatergic overdrive, through NMDA receptor-dependent signalling, is linked to the amplification and propagation of beta synchronisation across the CBT circuit, highlighting it as a potential biomarker and a promising therapeutic target in PD. Funding This research was supported by the 10.13039/501100001809National Natural Science Foundation of China (32271173, 82371256) and the Natural Science Foundation of Beijing Municipality (7242214, 7252213). This study was also supported by the 10.13039/501100004359Swedish Research Council (VR-M-2020-01652), the 10.13039/100017156Swedish e-Science Research Centre (SeRC), 10.13039/501100009252Science for Life Laboratory, KTH Digital Future, EU/Horizon 2020 No. 945539 (HBP 935 SGA3) and No. 101147319 (EBRAINS 2.0 Project), the European Union’s Research and Innovation Program Horizon Europe under grant agreement No. 101137289(the Virtual Brain Twin Project).
A temporal relationship between STN dysfunction and symptom onset is revealed and site- and frequency-specific stimulation strategies to address motor and non-motor symptoms in PD are supported.
Mathilde Bertrand, S. Chabardès, Jessy Hugues Dit Ciles et al.· npj Parkinson's Disease· 0 citations
Progressive, age-dependent remodeling of motor cortex somatotopic remodeling is demonstrated in 5XFAD mice, characterized by early expansion of specific simple movement cortical sites followed by deterioration of both complex and simple motor cortical maps as disease advances.
SE Moss, Cassandra C. Wolsh, Rmii Brown et al.· bioRxiv· 0 citations
It is shown that the mouse VNC feeds extensive Vglut2-defined projections into striato-thalamo-subthalamic and caudal medulla motor hubs and receives substantial input from the sensorimotor cortex and receives substantial input from the sensorimotor cortex.
J. Hartig, M. Friedrich, J. Signoret-Genest et al.· Nature Communications· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
