How Brain’s Pyramidal Neurons Differ in Autism and Schizophrenia

Layer 5 pyramidal neurons play a critical role in integrating and distributing information across neural circuits in the brain. These neurons are found in the outer layers of the brain and are particularly important in processing and relaying information. A recent study conducted by researchers from VIB-KU Leuven and the University of Dundee focused on two specific types of these neurons: intratelencephalic (IT) neurons and pyramidal tract (PT) neurons. Each type has distinct functions and synaptic properties that influence how they communicate within neural networks.

Using proteomics to study mouse neurons

The research team utilized proteomics, a technique for analyzing the protein composition of cells, to map the synaptic proteins of IT and PT neurons in mice. Synapses, the points of communication between neurons, contain a variety of proteins that determine how signals are transmitted. By comparing the synaptic proteins of these two neuron types, the team identified both shared and unique features.

These differences are not merely structural but are also functional. Variations in protein composition between IT and PT neurons could impact how they contribute to brain function and may explain their differential vulnerabilities to neurodevelopmental and psychiatric conditions.

"Mapping the synaptic protein composition of layer 5 neurons is an important step in understanding how these neurons are wired into neural circuits and how this process may be affected by neurodevelopmental disorders."

Prof. Joris de Wit

Implications for autism and schizophrenia

The study highlights that IT neurons might be more susceptible to disruptions linked to autism spectrum disorders. Further research supported by the Simons Foundation will explore how genes associated with autism might alter the synaptic composition and connectivity of IT neurons. Understanding these differences could provide insights into why certain neurons are more prone to being affected by these conditions, although the findings are still limited to preclinical models.

PT neurons, on the other hand, may have vulnerabilities tied to other neurological or psychiatric disorders. The research underscores the need to profile additional neuron types to develop a more comprehensive understanding of their roles in both health and disease.

Future research directions

The team aims to expand this synaptic profiling approach to include other neuron types across the brain. Such work could pave the way for identifying new targets for therapeutic interventions. However, the current study does not directly translate to human health as it was conducted on mouse neurons. Further studies are required to confirm whether these findings are applicable to humans.

Reference: Marcassa G, Dascenco D, Lorente-Echeverría B, et al. Synaptic signatures and disease vulnerabilities of layer 5 pyramidal neurons. Nat Commun. 2025;16(1):228. doi: 10.1038/s41467-024-55470-w

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