Credit: Redbird Research.

A molecular clue to schizophrenia may be hiding in the clear fluid that bathes the brain. And unusually, the same missing signal may also point toward a way of treating one of the disorder’s most stubborn problems: cognitive impairment.

Researchers at Northwestern University and Johns Hopkins University have identified a freely circulating form of a protein called α2δ-1 that appears at lower levels in the cerebrospinal fluid of people with schizophrenia. They then engineered a version of that protein, called SEAD1, and injected it into the brains of mice carrying a genetic alteration associated with schizophrenia. A single dose restored several abnormalities in their brain circuits and improved tests of memory and social behavior. The findings were published in Neuron.

The result offers an intriguing two-part strategy: use a biological marker to identify patients with a particular circuit problem, then give them a molecule designed to correct that same problem. In this case, a novel formulation based on the new findings could essentially alleviate some of the cognitive strain faced by schizophrenia patients.

“A lot of people with schizophrenia cannot integrate well into society because of these cognitive deficits,” Peter Penzes, the study’s senior author and a neuroscientist at Northwestern, said in the university’s press release.

A signal missing from spinal fluid

Antipsychotic drugs can substantially reduce hallucinations and delusions in schizophrenia patients who respond to such treatment, but the cognitive problems have proved harder to address. Problems with attention, working memory, planning and processing information can emerge early in schizophrenia and often persist despite treatment.

In an initial experiment, Northwestern researchers used mass spectrometry to compare cerebrospinal fluid from five people with schizophrenia and five unaffected controls. Among more than 1,400 detected proteins, several synaptic proteins differed between the groups. One such protein, known as α2δ-1, stood out partly because related datasets had also implicated it across several disorders involving cognitive impairment.

The team then tested the finding in independent groups. In 26 people within five years of their first psychotic episode, α2δ-1 levels were significantly lower than in 26 matched controls. A third analysis, using postmortem cerebrospinal fluid from 10 people with schizophrenia and seven controls, produced the same overall result.

The compound α2δ-1 is part of a calcium-channel complex on neurons. The surprise was that neurons also appear to cut the protein loose from the cell membrane and release it into their surroundings. In mouse brain tissue, neuronal stimulation increased that release. When researchers instead used an antibody to reduce soluble α2δ-1 by roughly half, mice performed worse on a working-memory task.

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That suggested the floating protein was not cellular debris. It was doing something.

Turning a biomarker into a treatment

The researchers engineered a soluble version of the protein called SEAD1. In cultured neurons and brain slices, it dampened excessive synchronized activity by strengthening parvalbumin interneurons, which are inhibitory cells that act rather like brakes on neuronal networks.

When analyzed under a microscope, SEAD1 preferentially accumulated around these interneurons and near the excitatory synapses feeding into them, apparently helping the inhibitory cells respond more strongly. The effect ultimately shifted neural circuits away from excessive excitation and toward a more balanced state.

The crucial test involved mice carrying a duplication of a region of chromosome 16 called 16p11.2. In people, that duplication substantially increases the risk of schizophrenia, although it accounts for only a small fraction of cases.

A single injection of SEAD1 into the mice’s anterior cingulate cortex restored excitatory connections onto parvalbumin neurons. It also rescued their poor performance in a novel-object memory task. Engineered male mutant mice, which showed reduced social approach, returned to approximately normal levels after treatment; female mice did not have a significant social deficit to begin with. SEAD1 did not simply make the animals more or less active.

“Our treatment reopens a crucial window to rewire connections in adult brains,” said Marc Dos Santos, the study’s first author. “The lack of brain plasticity is believed to be a key factor in the development of symptoms in schizophrenia. Reforming synapses could also be beneficial for other mental disorders, such as depression.”

The work fits into a growing effort to develop peptide and protein therapeutics that act more precisely on the molecular machinery of brain cells. Rather than broadly altering dopamine signaling, as most antipsychotics do, the researchers hope a SEAD1-derived therapy could strengthen a particular class of neurons whose malfunction has repeatedly been associated with schizophrenia.

Peptides — short chains of amino acids — and larger therapeutic proteins can sometimes mimic naturally occurring signaling molecules with considerably more specificity than small-molecule drugs. SEAD1 itself is a recombinant protein produced by the researchers and is not an approved drug or consumer peptide product. However, peptide-based experimental tools have become increasingly available. Independent suppliers maintaining dedicated catalogues of cognitive research compounds have also made a wider range of neuropeptides available to laboratories working in this field.

“Our discovery could solve these challenges by establishing the basis of a revolutionary and completely novel treatment strategy through a tandem biomarker-peptide therapeutic approach,” Penzes said.

Promising, but nowhere near a prescription

The basic idea behind this new research has precedents. A 2021 Science Advances study identified another secreted synaptic protein, NPTX2, that was reduced in cerebrospinal fluid from people with recent-onset schizophrenia and linked its loss to dysfunction of the same parvalbumin interneurons. More recently, researchers reported in Nature in 2025 that an engineered nanobody could reach the mouse brain and improve cognitive deficits caused by NMDA-receptor dysfunction.

The field is also moving beyond traditional dopamine-blocking drugs. In 2024, the Food and Drug Administration approved Cobenfy, the first approved schizophrenia treatment targeting cholinergic rather than dopamine receptors.

SEAD1 would represent a much more experimental step toward directly repairing dysfunctional circuits. Yet several obstacles remain. The human samples were relatively small. Cerebrospinal fluid also requires an invasive lumbar puncture. Most importantly, SEAD1 has so far been tested therapeutically only as a single injection directly into the brain of one genetic mouse model. The researchers do not yet know how long its effects last, what repeated dosing would do or whether it would work across the much broader biological diversity of schizophrenia.

For now, Penzes and Dos Santos have filed a provisional patent related to the findings.

“The next step for us would be to develop a blood biomarker to identify a subset of schizophrenia patients who can respond to this treatment,” Penzes said.