Biology subjects

Irinopoulou, T.

Publications and source records attributed to Irinopoulou, T..

3 recordsLinked to original sources

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↗

bioRxiv2019

Mice carrying a humanized Foxp2 knock-in allele show region-specific shifts of striatal Foxp2 expression levels

Genetic and clinical studies of speech and language disorders are providing starting points to unravel underlying neurobiological mechanisms. The gene encoding the transcription factor FOXP2 has been the first example of a gene involved in the development and evolution of this human-specific trait. A number of autosomal-dominant FOXP2 mutations are associated with developmental speech and language deficits indicating that gene dosage plays an important role in the disorder. Comparative genomics studies suggest that two human-specific amino acid substitutions in FOXP2 might have been positively selected during human evolution. A knock-in mouse model carrying these two amino acid changes in the endogenous mouse Foxp2 gene (Foxp2hum/hum) shows profound changes in striatum-dependent behaviour and neurophysiology, supporting a functional role for these changes. However, how this affects Foxp2 expression patterns in different striatal regions and compartments has not been assessed. Here, we characterized Foxp2 protein expression patterns in adult striatal tissue in Foxp2hum/hum mice. Consistent with prior reports in wildtype mice, we find that striatal neurons in Foxp2hum/hum mice and wildtype littermates express Foxp2 in a range from low to high levels. However, we observe a shift towards more cells with higher Foxp2 expression levels in Foxp2hum/hum mice, significantly depending on the striatal region and the compartment. As potential behavioural readout of these shifts in Foxp2 levels across striatal neurons, we employed a morphine sensitization assay. While we did not detect differences in morphine-induced hyperlocomotion during acute treatment, there was an attenuated hyperlocomotion plateau during sensitization in Foxp2hum/hum mice. Taken together, these results suggest that the humanized Foxp2 allele in a mouse background is associated with a shift in striatal Foxp2 protein expression pattern.

neuroscience↗

bioRxiv2018

KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels

The K+/Cl- co-transporter KCC2 (SLC12A5) regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in several neurological and psychiatric disorders including epilepsy, neuropathic pain and autism spectrum disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents was depolarized in KCC2 knockdown neurons, this shift was fully compensated by depolarization of their resting membrane potential. This effect was due to downregulation of Task-3 leak potassium channels that we show require KCC2 for membrane trafficking. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis that could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that concur to perturb network activity, thus offering novel targets for therapeutic intervention.

neuroscience↗