Caboche, J. | Search bioRxiv

bioRxiv2024

PYK2 in the dorsal striatum of Huntington disease R6/2 mouse model

Huntingtons disease (HD) is a devastating disease due to autosomal dominant mutation in the HTT gene. Its pathophysiology involves multiple molecular alterations including transcriptional defects. We previously showed that in HD patients and mouse model, the protein levels of the non-receptor tyrosine kinase PYK2 were decreased in the hippocampus and that viral expression of PYK2 improved the hippocampal phenotype. Here, we investigated the possible contribution of PYK2 in the striatum, a major brain region altered in HD. PYK2 mRNA levels were decreased in the striatum and hippocampus of R6/2 mice, a severe HD model. PYK2 protein levels were also decreased in the dorsal striatum of R6/2 mice and in the putamen of human patients. PYK2 knockout by itself did not result in motor symptoms observed in HD mouse models. Yet, we examined whether PYK2 deficiency participated in the R6/2 mice phenotype by expressing PYK2 in the dorsal striatum using AAV vectors. With an AAV1/Camk2a promoter, we did not observe significant improvement of body weight, clasping, motor activity and coordination (rotarod) alterations observed in R6/2 mice. With an AAV9/SYN1 promoter we found an improvement of body weight loss and a tendency to better rotarod performance. DARPP-32 immunofluorescence was increased following AAV9/SYN1-PYK2 injection compared to AAV9/SYN1-GFP, suggesting a possible partial beneficial effect on striatal projection neurons. We conclude that PYK2 mRNA and protein levels are decreased in the striatum as in hippocampus of HD patients and mouse models. However, in contrast to hippocampus, striatal viral expression of PYK2 has only a slight effect on the R6/2 model striatal motor phenotype. HighlightsO_LIHuntingtons disease is a lethal genetic disease altering striatum, cortex, and hippocampus C_LIO_LIRestoring PYK2 levels in hippocampus improved hippocampal phenotype of a Huntington mouse model C_LIO_LIWe show that PYK2 levels are decreased in the striatum of R6/2 mice and human patients C_LIO_LIViral expression of PYK2 in the striatum has only a small effect on R6/2 mouse model motor phenotype but improves weight loss C_LI

neuroscience↗

bioRxiv2021

Cell type- and region-specific modulation of cocaine seeking by micro-RNA-1 in striatal projection neurons

The persistent and experience-dependent nature of drug addiction may result in part from epigenetic alterations, including non-coding micro-RNAs (miRNAs), which are both critical for neuronal function and modulated by cocaine in the striatum. Two major striatal cell populations, the striato-nigral and striato-pallidal projection neurons, express respectively the D1 (D1-SPNs) and D2 (D2-SPNs) dopamine receptor, and display distinct but complementary functions in drug-evoked responses. However, a cell-type-specific role for miRNAs action has yet to be clarified. Here, we evaluated the expression of a subset of miRNAs proposed to modulate cocaine effects in the nucleus accumbens (NAc) and dorsal striatum (DS) upon sustained cocaine exposure in mice and showed that these selected miRNAs were preferentially up-regulated in the NAc. We then focused on miR-1 considering the important role of some of its predicted mRNA targets, such as fosb and npas4, in the effects of cocaine. We validated these targets in vitro and in vivo and further showed that overexpression of miR-1 in D1-SPNs of the DS reduced cocaine-induced CPP reinstatement, whereas it increased cue-induced reinstatement of cocaine-SA, without affecting other cocaine-mediated adaptive behavior. In addition, miR-1 overexpression in D2-SPNs of the DS reduced the motivation to self-administer cocaine but did not modify other measured behaviors. Together, our results highlight a precise cell-type- and region-specific control of relapse to cocaine-seeking behaviors by miR-1, and illustrate the importance of cell-specific investigations.

neuroscience↗