Striatal network modeling in Huntington's Disease.

Medium spiny neurons (MSNs) comprise over 90% of cells in the striatum. In vivo MSNs display coherent burst firing cell assembly activity patterns, even though isolated MSNs do not burst fire intrinsically. This activity is important for the learning and execution of action sequences and is characteristically dysregulated in Huntington's Disease (HD). However, how dysregulation is caused by the various neural pathologies affecting MSNs in HD is unknown. Previous modeling work using simple cell models has shown that cell assembly activity patterns can emerge as a result of MSN inhibitory network interactions. Here, by directly estimating MSN network model parameters from single unit spiking data, we show that a network composed of much more physiologically detailed MSNs provides an excellent quantitative fit to wild type (WT) mouse spiking data, but only when network parameters are appropriate for the striatum. We find the WT MSN network is situated in a regime close to a transition from stable to strongly fluctuating network dynamics. This regime facilitates the generation of low-dimensional slowly varying coherent activity patterns and confers high sensitivity to variations in cortical driving. By re-estimating the model on HD spiking data we discover network parameter modifications are consistent across three very different types of HD mutant mouse models (YAC128, Q175, R6/2). In striking agreement with the known pathophysiology we find feedforward excitatory drive is reduced in HD compared to WT mice, while recurrent inhibition also shows phenotype dependency. We show that these modifications shift the HD MSN network to a sub-optimal regime where higher dimensional incoherent rapidly fluctuating activity predominates. Our results provide insight into a diverse range of experimental findings in HD, including cognitive and motor symptoms, and may suggest new avenues for treatment

Enhancer RNAs are necessary and sufficient for activity-dependent neuronal gene transcription

Enhancer elements in DNA regulate gene expression programs important for neuronal fate and function, and are increasingly implicated in brain disease states. Enhancers undergo bidirectional transcription to generate non-coding enhancer RNAs (eRNAs), but the function of eRNAs in neuronal systems remains controversial. Here, we performed genome-wide characterization of transcribed enhancers from rat cortical neurons, revealing elevated sequence conservation, enriched localization near genes involved in neuronal or synaptic function, and correlated activity-dependent regulation of putative eRNA-mRNA pairs. Functional validation using a CRISPR-dCas9 fusion system to drive eRNA synthesis from enhancers produced corresponding increases in mRNA at linked genes. Focusing on eRNAs arising from enhancers at the Fos gene locus, we report that eRNA and mRNA correlate on a single-cell level, that CRISPR-targeted eRNA delivery to an enhancer is sufficient for mRNA induction, and that eRNA knockdown decreases mRNA and alters neuronal physiology. These results suggest that eRNAs regulate gene expression and neuronal function