Neuronal Hyperactivity Recruits the Immune System to Eliminate Synapses

Post by Shalana Atwell

The takeaway

Neuronal hyperactivity in the adult brain can trigger local synapse loss by recruiting the immune protein complement component 1q (C1q), which initiates a cascade that flags and removes synapses at specific terminals. In mouse hippocampal circuits, C1q-dependent pruning requires nearby antibody-producing B cells that secrete immunoglobulins, especially IgM, to mark vulnerable synapses for removal.

What's the science?

Synapse loss is tightly linked to cognitive decline in diseases such as Alzheimer’s disease (AD). Prior work showed that microglia and C1q mediate synaptic pruning; however, the mechanisms by which specific synapses are tagged and whether adaptive immune cells play a role in this process have not been characterized. This week in Science, Crowley and colleagues asked whether changing neuronal activity is sufficient to drive C1q-dependent synapse loss in adult hippocampal circuits and how immune proteins contribute to activity-dependent pruning. 

How did they do it?

The authors used chemogenetic tools called DREADDs (Designer Receptor Exclusively Activated by Designer Drugs) to bidirectionally control activity in defined hippocampal pathways. They injected an excitatory DREADD virus into the medial entorhinal cortex to selectively activate perforant pathway neurons that project to the dentate gyrus, and an inhibitory DREADD virus into the same pathway in an Alzheimer’s mouse model (J20 amyloid model) to dampen its hyperactivity. For five days, animals received daily injections of the designer drug clozapine-N-oxide (CNO) to specifically activate these engineered receptors, and the authors confirmed efficacy through in vivo neural recording (Neuropixels) and immediate early genes (e.g. c-FOS) related to neuronal activity. To further validate their findings, they used other models of hyperexcitability (kainic acid and subthreshold pentylenetetrazole) that induce seizure-like network activity and then measured C1q deposition and synapse density.

To uncover molecular changes, they applied multiple forms of spatial transcriptomics (Visium and Xenium) to hippocampal sections, focusing on differentially expressed genes and cell types around the dentate gyrus in activated versus control hemispheres. These analyses unexpectedly highlighted immunoglobulin genes, so the authors used RNAscope, immunohistochemistry, and high-resolution microscopy to visualize B-lineage cells and different antibody isotypes in cells adjacent to hyperactive circuits. Finally, they used several transgenic and pharmacological tools targeting B cells and antibodies (e.g. IgM knockout mice) to test whether secreted, antigen-specific immunoglobulins are required for activity-dependent C1q deposition and synapse loss.

What did they find?

Inducing hyperactivity in the perforant pathway in healthy mice produced a focal increase in C1q deposition in the activated projection zone and targeted loss of specific presynaptic terminals (VGLUT2-positive). This pattern suggests that local circuit activity can spatially direct where C1q accumulates and which synapses are selectively removed, rather than causing global synaptic damage. Inhibiting perforant pathway hyperactivity in J20 amyloid mice reduced C1q accumulation, decreased amyloid-β immunoreactivity, and partially restored postsynaptic markers, supporting the relationship between hyperactivity and C1q deposition in disease. In mice lacking a functional C1q protein (C1qa knockout), chemogenetic activation increased c-Fos expression but no longer produced VGLUT2 terminal loss, demonstrating that C1q itself is required for this form of activity-dependent presynaptic pruning.

Spatial transcriptomics in activated wild-type brains revealed strongly upregulated immunoglobulin genes, indicating local antibody-secreting cells near the hyperactive pathway. RNAscope, spatial transcriptomics, and immunostaining identified B-lineage cells adjacent to activated hippocampal regions. Imaging revealed that IgM localized near C1q-positive VGLUT2 terminals, suggesting that locally produced IgM antibodies help recruit C1q to specific synapses during periods of increased activity. Functionally, mice lacking B cells or IgM, or with restricted B-cell receptor specificity (B cells all recognize the same kind of antigen), failed to show the typical activity-dependent C1q deposition and VGLUT2 loss after hyperactivity. This indicates that antigen-specific, secreted IgM from B-lineage cells is required to enable C1q-mediated synapse elimination in the perforant pathway.

What's the impact?

This study is the first to demonstrate that neuronal hyperactivity is sufficient to drive C1q-dependent synapse loss in the adult brain and that local B-lineage cells and their IgM antibodies are key enablers of this process. By revealing that adaptive immune cells can respond to circuit activity and tag synapses for C1q-mediated pruning, it broadens our understanding of how innate and adaptive immunity collaborate to sculpt adult neural circuits. Further, the work suggests that in disorders with early hippocampal hyperexcitability such as Alzheimer's disease, modulating neuronal activity or interrupting IgM-C1q interactions at synapses could be promising strategies to limit synapse loss and preserve cognitive function.

Access the original scientific publication here.

How Bilingual Brains Handle Grammar in Two Languages at Once

Post by Amanda Engstrom

The takeaway

The bilingual brain must compute different grammar rules for different languages at millisecond resolution. This computation relies on a shared brain network spanning the left frontal and temporal lobes, using flexible, reusable rules rather than a separate network for each language.

What's the science?

Human language requires the speaker to alter the pronunciation of words to account for changing information such as the plural form of an object, but the phonological rules for this are different across languages. This raises the question as to whether the brain utilizes language-specific neural systems or if it relies on a shared abstract mechanism that generalizes across linguistic contexts. Prior brain imaging work on this question has produced mixed results and has mostly examined language comprehension, leaving open whether the same holds true during the split-second demands of planning and producing speech. This week in Journal of Neuroscience, Chen and colleagues aimed to resolve this by using magnetoencephalography (MEG) to track millisecond-scale brain activity in Spanish/English bilinguals, using a task designed to separate the mental act of changing a word's grammatical form from other factors like the word's meaning or how it sounds, allowing them to pinpoint when and where this computation occurs in the brain as bilinguals produced singular and plural nouns in both languages.

How did they do it?

The authors recruited 23 highly proficient Spanish-English bilinguals to complete a phrase-completion task: participants saw a written noun (e.g., "boat"), then heard a spoken cue ("one," "two," or "say") prompting them to produce the singular form, plural form, or simply repeat the word aloud. The task varied language, whether grammatical change was needed, and whether that change altered the word's sound, all independently of one another.

While participants performed the task, the authors recorded brain activity using MEG, a non-invasive technique that detects magnetic fields from active neurons at a millisecond timescale, critical for capturing the split-second planning between hearing a cue and speaking. They also collected structural MRI scans and combined them with MEG data through source localization, which estimates where in the brain each signal originated using each participant's own anatomy. First, they compared brain activity when transforming versus simply repeating a word. Second, they trained a computer algorithm to recognize that activity pattern in one language (e.g., English) and then tested whether it could detect the same pattern in the other (Spanish). Successful detection across languages ("cross-decoding") would show that English and Spanish rely on a common neural code, rather than separate systems.

What did they find?

The authors found that transforming a word's grammatical form (e.g., "boat" to "boats") activated the left frontal and temporal regions much more strongly than simply repeating a word, even for words that don't change sound when pluralized (like "tuna/tuna"). This suggests that these brain regions carry out grammatical transformation as an abstract computation, rather than one tied to a specific sound pattern. Comparing English and Spanish separately, both languages activated nearly the same brain regions, with Spanish showing activity about 110 milliseconds earlier than English. A decoding algorithm trained to detect grammatical transformation in one language successfully detected it in the other, suggesting that English and Spanish rely on a shared brain mechanism for this computation rather than two separate systems, with the timing difference simply reflecting how quickly each language can be processed. Finally, this same pattern held even for words that don't exist in either language, and cognates (like "chocolate/chocolate") showed no added advantage over other real words. This suggests that the brain's grammar system is highly generalizable: it can apply grammatical rules to entirely novel words and doesn't depend on having a matching or overlapping vocabulary entry to work with.

What's the impact?

This study found that Spanish-English bilinguals engage in a shared left frontal-temporal network to process the grammatical transformation of pluralizing a word in both languages, suggesting the bilingual brain uses flexible, reusable rules rather than separate networks per language. These findings support a growing body of work showing that the brain favors efficient, generalizable abstract computations that can be reused across different contexts. Further, this study demonstrates how bilingualism can be used to interrogate general principles of neural organization. 

Access the original scientific publication here

Time Perception in Obsessive-Compulsive Disorder

Post by Anastasia Sares

The takeaway

In a preliminary study designed to understand how people with obsessive-compulsive disorder may differ in time processing, the authors found that while objective time perception and movement ability were intact, subjective time perception (including time management, time knowledge, and time experience) was significantly impacted.

What's the science?

Obsessive Compulsive Disorder (OCD) is a condition in which a person experiences recurring worries (obsessions) and enacts certain behaviors (compulsions) to try and manage these worries. OCD shares some features with depression (for example, some depression medications that act on serotonin can also be used to treat OCD). It additionally shares features with movement disorders such as Tourette’s, where differences in brain function cause involuntary actions that are difficult for the person to control. 

People with OCD can take longer to complete certain tasks and experience difficulties with time management. However, it is currently unclear what contributes to this. One possibility is that people with OCD have more difficulty controlling their movements, which means that doing things takes more time. Another possibility is that their objective time perception is altered—they might be less able to estimate time passing due to differences in time-keeping mechanisms in the brain. Finally, a third possibility is that people with OCD differ in their subjective experience of time, which could include difficulty making plans or realizing how much time they have spent on a task.

Recently, in an exploratory study published in European Archives of Psychiatry and Clinical Neuroscience, Mavrogiorgou and colleagues tested both objective and subjective time perception, along with movement ability and depression/anxiety symptoms, to better understand whether OCD uniquely contributes to altered time processing.

How did they do it?

In this exploratory study, the authors recruited 20 participants with OCD and 20 healthy participants of similar ages and genders. They ran them through a battery of tests, including questionnaires to establish the severity of OCD symptoms, questionnaires for depression and anxiety symptoms, measures of movement ability, experimental tests to measure more concrete/objective aspects of time perception, and questionnaires about subjective aspects of time perception.

The objective time perception tasks included flicker fusion frequency, which presents a blinking light that flickers at faster and faster frequency until the participant indicates that they perceive it to be stable and not flickering anymore—this measures the timing resolution of their visual perception. Another was the Chronotest, where participants are presented with a light stimulus and asked to estimate how long it was on, in seconds. They are also asked to reproduce different time intervals by turning a light on for that amount of time.

What did they find?

Participants with OCD were not significantly different from the healthy controls in their objective time perception, and there was only a slight trend for a difference in movement ability. In contrast, subjective time measures such as time knowledge, time experience, and time management were significantly impaired in OCD, and were correlated with OCD symptoms—in other words, those with more severe OCD had poorer subjective time perception. Subjective time perception was also correlated with depression scores, both in people with OCD and in the healthy control group, but some influence of OCD symptoms remained even after controlling for depression, anxiety, and movement issues, specifically on time management. It’s worth noting that subjective time perception was measured using a questionnaire, while the objective time measures were done using experiments, so self-perception had more of a chance to influence the results.

What's the impact?

Since this is an exploratory study, it should be treated as preliminary, but it has the potential to increase our knowledge of a lesser-known aspect of OCD. If these results hold, it means that there are time perception differences in OCD that are not related to movement difficulties or depression/anxiety symptoms.

Access the original scientific publication here.