GFR-α1 Expression in Substantia Nigra Increases Bilaterally Following Unilateral Striatal GDNF in Aged Rats and Attenuates Nigral Tyrosine Hydroxylase Loss Following 6-OHDA Nigrostriatal Lesion.

Glial cell line-derived neurotrophic factor (GDNF) improved motor function in Parkinson's disease (PD) patients in Phase I clinical trials, and these effects persisted months after GDNF discontinuation. Conversely, phase II clinical trials reported no significant effects on motor improvement vs placebo. The disease duration and the quantity, infusion approach, and duration of GDNF delivery may affect GDNF efficacy in PD treatment. However, identifying mechanisms activated by GDNF that affect nigrostriatal function may reveal additional avenues to partially restore nigrostriatal function. In PD and aging models, GDNF affects tyrosine hydroxylase (TH) expression or phosphorylation in substantia nigra (SN), long after a single GDNF injection in striatum. In aged rats, the GDNF family receptor, GFR-α1, increases TH expression and phosphorylation in SN. To determine if GFR-α1 could be a mechanistic link in long-term GDNF impact, we conducted two studies; first to determine if a single unilateral striatal delivery of GDNF affected GFR-α1 and TH over time (1 day, 1 week, and 4 weeks) in the striatum or SN in aged rats, and second, to determine if soluble GFR-α1 could mitigate TH loss following 6-hydroxydopamine (6-OHDA) lesion. In aged rats, GDNF bilaterally increased ser31 TH phosphorylation and GFR-α1 expression in SN at 1 day and 4 weeks after GDNF, respectively. In striatum, GFR-α1 expression decreased 1 week after GDNF, only on the GDNF-injected side. In 6-OHDA-lesioned rats, recombinant soluble GFR-α1 mitigated nigral, but not striatal, TH protein loss following 6-OHDA. Together, these results show GDNF has immediate and long-term impact on dopamine regulation in the SN, which includes a gradual increase in GFR-α1 expression that may sustain TH expression and dopamine function therein.

"Teaching old dogs new tricks": targeting neural extracellular matrix for normal and pathological aging-related cognitive decline.

Cognitive decline is a feature of normal and pathological aging. As the proportion of the global aged population continues to grow, it is imperative to understand the molecular and cellular substrates of cognitive aging for therapeutic discovery. This review focuses on the critical role of neural extracellular matrix in the regulation of neuroplasticity underlying learning and memory in another under-investigated "critical period": the aging process. The fascinating ideas of neural extracellular matrix forming a synaptic cradle in the tetrapartite synapse and possibly serving as a substrate for storage of very long-term memories will be introduced. We emphasize the distinct functional roles of diffusive neural extracellular matrix and perineuronal nets and the advantage of the coexistence of two structures for the adaptation to the ever-changing external and internal environments. Our study of striatal neural extracellular matrix supports the idea that chondroitin sulfate proteoglycan-associated extracellular matrix is restrictive on synaptic neuroplasticity, which plays important functional and pathogenic roles in early postnatal synaptic consolidation and aging-related cognitive decline. Therefore, the chondroitin sulfate proteoglycan-associated neural extracellular matrix can be targeted for normal and pathological aging. Future studies should focus on the cell-type specificity of neural extracellular matrix to identify the endogenous, druggable targets to restore juvenile neuroplasticity and confer a therapeutic benefit to neural circuits affected by aging.

Erasure of striatal chondroitin sulfate proteoglycan-associated extracellular matrix rescues aging-dependent decline of motor learning.

Cognitive decline is a feature of aging. Accumulating evidence suggests that the brain extracellular matrix (ECM) is involved in the process of aging-dependent cognitive impairment and neurodegeneration by regulating synaptic neurotransmission and affecting neuroplasticity. Age-related changes in brain structure and cognition are not uniform across the whole brain. Being one of the most vulnerable brain regions to aging-dependent alterations, striatum is integral to several central nervous system functions, such as motor, cognition, and affective control. However, the striatal ECM is largely understudied. We first describe 2 major types of chondroitin sulfate proteoglycan (CSPG)-associated ECM in striatum: perineuronal nets and diffusive ECM. Both types of ECM accumulate in an aging-dependent manner. The accumulation of CSPG-associated ECM correlates with aging-dependent decline in striatum-related cognitive functions, including motor learning and working memory. Enzymatic depletion of CSPG-associated ECM in aged mice via chondroitinase ABC significantly improves motor learning, suggesting that changes in neural ECM CSPGs regulate striatal plasticity. Our study provides a greater understanding of the role of neural ECM underlying striatal plasticity, which is an important precursor to design appropriate therapeutic strategies for normal and pathologic aging.

Cre-dependent AAV vectors for highly targeted expression of disease-related proteins and neurodegeneration in the substantia nigra.

Recombinant adeno-associated virus (AAV) vectors are a popular genetic approach in neuroscience because they confer such efficient transgene expression in the brain and spinal cord. A number of studies have used AAV to express pathological disease-related proteins in the dopaminergic neurons of the substantia nigra in situ ( e.g., α-synuclein to model aspects of Parkinson's disease). The neuropathology and neurodegeneration of Parkinson's disease occur in a circumscribed pattern in the brain, and one of the most important goals of any gene transfer study is accurate, pinpoint targeting. By combining Cre recombinase-dependent AAVs in Cre-driver rats in which Cre is expressed only in the tyrosine hydroxylase neurons, we have achieved more highly targeted expression of several disease-relevant neuropathological proteins in the substantia nigra pars compacta than using constitutive expression AAV vectors. Alpha-synuclein, tau, transactive response DNA-binding protein of 43 kDa, or the control fluorescent protein yellow fluorescent protein was individually expressed to induce highly targeted, dopaminergic neuron-specific neurodegeneration models. The refined targeting foreshadows a next-generation disease modeling system for expressing neurodegenerative disease-related proteins in a disease-relevant manner. We foresee specific utilities of this in vivo AAV vector targeting of pathological proteins to a well-defined and well-demarcated cell population.-Grames, M. S., Dayton, R. D., Jackson, K. L., Richard, A. D., Lu, X., Klein, R. L. Cre-dependent AAV vectors for highly targeted expression of disease-related proteins and neurodegeneration in the substantia nigra.