How CRISPR Is Changing The Way We Study The Brain

Dominic Borkelmans
Aug 7
7 min read

Few tools have shifted the pace of neuroscience like CRISPR. In just over a decade, it has gone from a microbial defense mechanism to one of the most powerful instruments for editing, modulating, and tracking genetic activity in the brain. Researchers can now turn genes on or off, rewrite DNA without breaking it, and trace how brain cells develop, all with unprecedented precision. These capabilities are laying the groundwork for new therapies targeting the roots of neurological disease.

A recent review by Kalamakis and Platt, published in Neuron, maps the current landscape of CRISPR applications in neuroscience. It covers everything from transcriptional modulation and organoid modeling to in vivo editing and molecular recording. This article walks through the key sections of that review, highlighting how each CRISPR innovation is expanding the experimental and therapeutic frontier of brain research.

Transcriptional Modulation and Precision Editing

CRISPR is not limited to just cutting DNA. A growing subset of CRISPR technologies allows scientists to modulate gene activity or rewrite the genome without making double-strand breaks. Catalytically inactive Cas enzymes (dCas9, dCas12, dCas13) act as programmable delivery vehicles, bringing transcriptional activators or repressors to specific genes. This lets researchers turn genes on or off with fine control, what’s known as CRISPRa or CRISPRi. Base editors and prime editors expand this toolkit, enabling single-letter DNA changes and precise edits without triggering cellular repair pathways.

These approaches have quickly gained traction in neuroscience. dCas9-based activators have been used to model neurological diseases linked to reduced gene expression, offering a path to rescue phenotypes by restoring endogenous activity. Similarly, CRISPR interference has been applied to silence genes involved in synaptic function, addiction, or neurodevelopmental disorders, without the irreversible effects of full knockouts. Researchers are also using these tools to guide cell fate, such as converting glial cells into neurons, or to orchestrate the differentiation of stem cells into defined neuronal types.

The paper highlights several applications where precision matters. One example is the use of CRISPRa to upregulate genes affected by haploinsufficiency, a common feature in brain disorders like schizophrenia or autism. Another compelling study showed how base editing was used to downregulate huntingtin (HTT) gene expression in a mouse model of Huntington’s disease. By targeting the HTT promoter, researchers achieved a stable reduction in the toxic protein without damaging the gene itself, pointing to a safer and more adaptable approach to therapeutic editing.

CRISPR in Stem Cells and Brain Organoids

One of the most transformative uses of CRISPR in neuroscience lies in how we model the human brain. Traditional cell lines and animal models often fall short when it comes to capturing the complexity of human neural development and disease. CRISPR has changed this by enabling precise genetic edits in stem cells, including induced pluripotent stem cells (iPSCs) derived from patients. These cells can be differentiated into neurons or assembled into brain-like organoids, creating human-relevant systems for studying gene function, development, and pathology.

Such platforms offer several advantages. Because iPSCs are mitotic, they are compatible with high-efficiency editing strategies like homology-directed repair. This allows researchers to introduce or correct disease-associated mutations, tag proteins with fluorescent markers, or engineer conditional alleles. In brain organoids, CRISPR tools have been used to delete specific genes, rewire signaling pathways, or model the effects of ancient human gene variants. This can bridge the gap between reductionist cell cultures and the complexity of in vivo systems, especially valuable for studying neurodevelopmental and neurodegenerative disorders.

The paper highlights an exciting example of this approach: the deletion of the human-specific gene NOTCH2NL in embryonic stem cells. The loss of  NOTCH2NL accelerated neuronal differentiation in organoids, providing insight into how this gene may have shaped human brain evolution. In another study, researchers introduced the Neanderthal variant of the NOVA1 gene into iPSCs, which led to changes in synaptic protein interactions and glutamatergic signaling. These experiments show that CRISPR can be used not only to model disease, but also to probe the genetic roots of our cognitive traits.

Engineering Animal Models with Zygote Editing

Creating genetically modified animals used to be a long and complex process. Traditional methods rely on embryonic stem cells and extensive breeding, often taking over a year to generate a single knockout line. CRISPR has dramatically accelerated this timeline. By delivering Cas9 and guide RNAs directly into fertilized zygotes, typically through microinjection or electroporation, researchers can now generate gene-edited animals in a single step. This editing approach is fast, scalable, and increasingly applied.

The simplicity of this method has made it a go-to strategy for generating knockout or knockin models in neuroscience. Cas9 ribonucleoproteins can be delivered into one-cell embryos to induce precise mutations that are carried through the germline. Electroporation has further streamlined the process, allowing for high-efficiency delivery without the need for specialized microinjection equipment. These advances have enabled the creation of conditional alleles, fluorescent reporters, and even complex edits involving multiple genes.

As noted in the review, zygote editing has opened the door to modeling neurological disease across many animal models. For example, it was used to generate mice with a mutation in the autism-linked gene CHD8, producing animals with altered social behavior and striatal circuit function. Beyond mice, CRISPR-based zygote editing is now being applied to rats, pigs, non-human primates, and other models with greater physiological relevance to humans. This shift is not just technical, it’s expanding the experimental toolkit available for studying complex brain disorders in systems that better reflect human biology.

Editing the Brain in Living Animals

CRISPR’s potential isn’t limited to embryos or petri dishes, it can also be used directly in the brains of living animals. By delivering gene-editing components into specific brain regions, researchers can knock out, activate, or repress genes in targeted cells with spatial and temporal precision. This allows for rapid, flexible experiments that bypass the need for breeding transgenic lines and enables scientists to study how genes influence behavior, memory, and disease processes in real time.

Several delivery methods are currently used to bring CRISPR into the brain. These include viral vectors like AAVs, in utero electroporation, and direct injection of Cas9 RNPs. Once inside the brain, CRISPR can be directed to specific neuronal subtypes or circuits using cell-type-specific promoters or inducible systems. Researchers have used this approach to study topics from synaptic plasticity to addiction-related gene networks. It allows for high throughput experiments, editing different genes in different regions within the same animal.

The paper describes one influential example: using in utero electroporation to knock out the Tbr2 gene in mouse neuronal progenitors. This led to a reduction in basal progenitor cells and an increase in differentiated neurons, revealing how Tbr2 controls cortical development. Other studies have shown how CRISPR-mediated disruption of the Grin1 gene in postnatal neurons impairs synaptic transmission. These experiments underscore CRISPR’s power to causally link genes to brain function, within the brain itself.

Uncovering Disease Pathways with CRISPR Screens

One of the most powerful shifts CRISPR has enabled in neuroscience is the rise of genome-wide pooled screens. These high-throughput approaches use large libraries of guide RNAs to perturb thousands of genes at once, allowing researchers to uncover the molecular pathways that shape neuronal survival, function, or disease. When applied to iPSC-derived neurons, astrocytes, or microglia, these screens make it possible to systematically map how genetic variation influences brain cell behavior.

The core idea is simple. Introduce a diverse pool of CRISPR tools into a population of cells, link each perturbation to a barcode, and then sort or sequence the cells based on a trait of interest. In neurons, this could mean identifying genes that protect against oxidative stress or regulate synaptic function. In glia, it might involve tracking regulators of inflammation or phagocytosis. These screens can use knockout (CRISPR-Cas9), repression (CRISPRi), or activation (CRISPRa) to incite gene function from multiple angles.

The authors highlight several impactful examples. In one study, researchers used CRISPRi and CRISPRa screens in iPSC-derived neurons to identify genes involved in lysosomal failure, a process linked to Parkinson’s disease. Another screen pinpointed regulators of PRKN and found new pathways tied to neurodegeneration. Similar approaches have been used to discover modifiers of tau expression in Alzheimer’s models, and genes that shape astrocyte and microglial reactivity. Together, these studies show how pooled CRISPR screens are becoming a go-to strategy for decoding complex brain disorders at scale.

Tracing Brain Development with CRISPR Barcodes

Beyond editing and modulation, CRISPR is now being used as a tool for memory. New systems allow researchers to “write” biological information directly into DNA, creating molecular barcodes that track how cells develop, divide, and change over time. This emerging capability, known as lineage tracing and molecular recording, is especially powerful in neuroscience, where understanding the origins and trajectories of different brain cell types is key to decoding development and disease.

The concept relies on engineered CRISPR systems that generate mutations in designated genomic loci in a programmable, time-sensitive way. Each cell accumulates a unique pattern of edits, like a biological timestamp, that can later be decoded through single-cell sequencing. These patterns reveal lineage relationships and cellular histories, offering insight into how neurons and glia diversify, migrate, and assemble into circuits. Variants of these systems can even record transient events like gene expression or neural activity.

The authors point to tools like scGESTALT and MEMOIR that have begun to apply these ideas to brain tissue. In one example, researchers used a CRISPR-based barcode system in organoids to track neural progenitor lineages and understand how clonal dynamics influence cortical structure. Other approaches use in situ sequencing to capture both lineage and gene expression within intact brain slices. While still early, these technologies promise to map not just the structure of the brain, but its developmental logic, one editable barcode at a time.

Conclusion

CRISPR has rapidly evolved from a genetic editing tool into a full-spectrum platform for investigating and engineering the brain. From rewriting single DNA bases to recording cellular histories, its versatility is reshaping how we model, probe, and potentially treat neurological disease. As these tools grow more precise and accessible, they’re allowing neuroscientists to ask questions that were once out of reach. Technical hurdles remain, but the path forward is clear. CRISPR is becoming foundational to the future of brain science.