## 3 Discussion
Nonetheless, recent studies comparing the transcriptomic signatures of astrocyte reactivity in rodent and human models have identified both commonalities and species-specific gene signatures [48; 49]. While there are commonalities, distinct gene expression programs have been identified. For instance, human astrocytes are more susceptible to oxidative stress and demonstrate stronger activation of the antigen presentation pathway under inflammatory conditions. In contrast, mouse astrocytes show unique features, such as the induction of a molecular program for neural repair under hypoxia [44]. These observations underscore the fact that species-specific differences are to be expected when comparing mouse and human astrocytes. Thus, the results of our study may reflect partially divergent regulation of astrocyte reactivity between these species, which is an important consideration for translating findings from rodent models to humans. Interestingly, previous studies using postmortem human brain tissue from AD patients have suggested a modest increase in proinflammatory genes in astrocytes and, more strikingly, a significant decrease in the expression of homeostatic genes involved in synapse regulation. Based on these findings, we further characterized the role of 3222401L13 Rik and _ENSG00000272070_ in neuronal support functions. However, we acknowledge the importance of elucidating the role of these lncRNAs in inflammatory processes in future research. The use of alternative, more complex human models, such as brain organoids, could also provide more insight into similarities and differences between the mouse and human lncRNA with regard to neuronal support and the regulation of inflammatory pathways. Our findings demonstrate that 3222401L13 Rik, as well as its human homolog, play crucial roles in maintaining the expression of several genes critical for neuronal and synaptic support within astrocytes. These include the glutamate transporters Glt1 and Glast, as well as genes controlling synaptic plasticity, such as Nrxn1. Consistent with this, the knockdown of 3222401L13 Rik impaired glutamate uptake and regulation of intracellular Ca\({}^{2+}\) levels in astrocytes. Additionally, astrocytes lacking 3222401L13 Rik were unable to efficiently support neurons, as evidenced by altered neuronal network plasticity and decreased neuronal spine density. Although specific data for _3222401L13 Rik_ or _ENSG00000272070_ are currently lacking, previous studies have shown that lncRNAs could regulate key cellular functions in astrocytes, including glutamate metabolism, calcium signaling, and neuronal network homeostasis [22; 50; 51; 25]. One mechanism by which lncRNAs control gene expression is through interactions with DNA, particularly in gene-promoter regions, and with proteins, thereby orchestrating the function of transcriptional regulators [13]. Bioinformatic analysis revealed that half of the transcripts downregulated upon _3222401L13 Rik_ knockdown contained binding regions for _3222401L13 Rik_ in their promoter regions, suggesting that these might be direct targets. Future work will be required to confirm these DNA-lncRNA interactions experimentally. Among these potential targets is Npas3, a transcription factor associated with neuropsychiatric disorders characterized by impaired neuronal plasticity, such as schizophrenia [52; 53; 54; 55; 56]. Our study shows that _3222401L13 Rik_ regulates _Npas3_, which is noteworthy since _Npas3_ is highly expressed in astrocytes, and its deficiency induces synaptic deficits in neurons [37]. Moreover, the affected pathways and gene networks identified in this study closely resemble the downregulated genes and pathways observed after the knockdown of _3222401L13 Rik_, including terms like \"synapse organization\", \"neurotransmitter transport\", and \"synapse assembly\". Accordingly, we demonstrate that overexpression of _Npas3_ can rescue both molecular and functional deficits resulting from the knockdown of _3222401L13 Rik_.