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Information in pallidal neurons increases with parkinsonian severity.

ABSTRACT: The motor symptoms of Parkinson's disease (PD) present with pathological neuronal activity in the basal ganglia. Although neuronal firing rate changes in the globus pallidus internus (GPi) and externus (GPe) are reported to underlie the development of PD motor signs, firing rates change inconsistently, vary confoundingly with some therapies, and are poor indicators of symptom severity.We explored the relationship between parkinsonian symptom severity and the effectiveness with which pallidal neurons transmit information. We quantify neuronal entropy and information - alternatives to firing rate and correlations respectively - in and between GPe and GPi neurons using a progressive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, non-human primate model of PD.Neuronal entropy and symptom severity were not linearly correlated: in both pallidal segments, entropy increased from naive to moderate parkinsonism, but decreased with further progression to the severely parkinsonian condition. In contrast, information transmitted from GPe to GPi increased consistently with symptom severity. Furthermore, antidromic information from GPi to GPe increased substantially with symptom severity. Together, these findings suggest that as parkinsonian severity increases, more and more information enters GPe and GPi from common sources, diminishing the relative importance of the orthodromic GPe to GPi connection.With parkinsonian progression, the direct and indirect pathways lose their independence and start to convey redundant information. We hypothesize that a loss of parallel processing impairs the ability of the network to select and implement motor commands, thus promoting the hypokinetic symptoms of PD.

SUBMITTER: Dorval AD

PROVIDER: S-EPMC4631644 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Information in pallidal neurons increases with parkinsonian severity.

Dorval Alan D AD Muralidharan Abirami A Jensen Alicia L AL Baker Kenneth B KB Vitek Jerrold L JL

Parkinsonism & related disorders 20150926 11

<h4>Introduction</h4>The motor symptoms of Parkinson's disease (PD) present with pathological neuronal activity in the basal ganglia. Although neuronal firing rate changes in the globus pallidus internus (GPi) and externus (GPe) are reported to underlie the development of PD motor signs, firing rates change inconsistently, vary confoundingly with some therapies, and are poor indicators of symptom severity.<h4>Methods</h4>We explored the relationship between parkinsonian symptom severity and the ...[more]

PMID: 26433544

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Project description:The external (GPe) and internal (GPi) segments of the primate globus pallidus receive dopamine (DA) axonal projections arising mainly from the substantia nigra pars compacta and this innervation is here described based on tyrosine hydroxylase (TH) immunohistochemical observations gathered in the squirrel monkey (Saimiri sciureus). At the light microscopic level, unbiased stereological quantification of TH positive (+) axon varicosities reveals a similar density of innervation in the GPe (0.19 ± 0.02 × 10(6) axon varicosities/mm(3) of tissue) and GPi (0.17 ± 0.01 × 10(6)), but regional variations occur in the anteroposterior and dorsoventral axes in both GPe and GPi and along the mediolateral plane in the GPe. Estimation of the neuronal population in the GPe (3.47 ± 0.15 × 10(3) neurons/mm(3)) and GPi (2.69 ± 0.18 × 10(6)) yields a mean ratio of, respectively, 28 ± 3 and 68 ± 15 TH+ axon varicosities/pallidal neuron. At the electron microscopic level, TH+ axon varicosities in the GPe appear significantly smaller than those in the GPi and very few TH+ axon varicosities are engaged in synaptic contacts in the GPe (17 ± 3%) and the GPi (15 ± 4%) compared to their unlabeled counterparts (77 ± 6 and 50 ± 12%, respectively). Genuine synaptic contacts made by TH+ axon varicosities in the GPe and GPi are of the symmetrical and asymmetrical type. Such synaptic contacts together with the presence of numerous synaptic vesicles in all TH+ axon varicosities observed in the GPe and GPi support the functionality of the DA pallidal innervation. By virtue of its predominantly volumic mode of action, DA appears to exert a key modulatory effect upon pallidal neurons in concert with the more direct GABAergic inhibitory and glutamatergic excitatory actions of the striatum and subthalamic nucleus. We argue that the DA pallidal innervation plays a major role in the functional organization of the primate basal ganglia under both normal and pathological conditions.

Project description:Rationale: Contactin-associated protein-like 4 (CNTNAP4) belongs to the neurexin superfamily and has critical functions in neurological development and synaptic function. Loss of CNTNAP4 in interneurons has been linked to autism, schizophrenia, and epilepsy. CNTNAP4 is also highly enriched in dopaminergic (DA) neurons in the substantia nigra (SN), however, few studies have investigated the role of CNTNAP4 in DA neurons, and whether CNTNAP4 deficiency in DA neurons contributes to Parkinson's disease (PD) remains unclear. Methods: Effects of CNTNAP4 knockdown or overexpression on the DA MN9D cell line were assessed via Western blotting, immunocytochemistry, and RNA sequencing. An in vivo animal model, including CNTNAP4 knockout mice and stereotaxic injections of adeno-associated viral short-hairpin RNA with the tyrosine-hydroxylase promotor to silence CNTNAP4 in the SN, as well as the resulting physiological/behavioral effects, were evaluated via behavioral tests, Western blotting, immunohistochemistry, and transmission electron microscopy. Enzyme-linked immunosorbent assays (ELISAs) were performed to examine the cerebrospinal fluid (CSF) and plasma CNTNAP4 concentrations in PD patients. Results: We demonstrated that CNTNAP4 knockdown induced mitophagy and increased α-synuclein expression in MN9D cells. CNTNAP4 knockdown in the SN induced PD-like increases in SN-specific α-synuclein expression, DA neuronal degeneration, and motor dysfunction in mice. In addition, CNTNAP4 knockdown in SN-DA neurons increased autophagosomes and reduced synaptic vesicles in the SN. Furthermore, CNTNAP4 knockout mice showed movement deficits, nigral DA degeneration, and increased autophagy, which were consistent with the SN-specific knockdown model. We also found that CSF and plasma CNTNAP4 expression was increased in PD patients; in particular, plasma CNTNAP4 was increased in male PD patients compared with controls or female PD patients. Conclusion: Our findings suggest that CNTNAP4 deficiency may initiate phenotypes relevant to PD, of which we elucidated some of the underlying mechanisms.

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Information in pallidal neurons increases with parkinsonian severity.

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Information in pallidal neurons increases with parkinsonian severity.

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