TMEM151A in forebrain excitatory neurons negatively regulates seizure susceptibility

Abstract

Objective

Transmembrane proteins play essential roles in neuronal function, yet many remain poorly characterized.
Transmembrane protein 151A
(
TMEM151A
) was identified in 2021 as a disease‐associated gene linked to paroxysmal neurological disorders. Despite its broad expression in the central nervous system, its role in neuronal network activity remains unclear. This study aims to determine the cell type‐specific expression pattern of
Tmem151a
and to investigate its functional involvement in seizure pathophysiology.



Methods

Cell‐type specific expression of
Tmem151a
was examined using RNAscope in situ hybridization combined with immunohistochemistry. Seizure susceptibility was assessed by pentylenetetrazol (PTZ) challenge and cortical electrostimulation in
Tmem151a
‐knockout mice on a C57BL/6J background, with electroencephalographic recordings confirming seizure activity. The hippocampal kindling model was used to evaluate epileptogenesis in
Tmem151a
‐knockout,
CaMKIIa
‐conditional knockout, and
Olig2
‐conditional knockout mice.
TMEM151A
overexpression in forebrain was achieved by intravenous delivery of adeno‐associated virus (AAV‐PHP.eB) in
Emx1
‐
Cre
mice, followed by hippocampal kindling analysis.



Results

In mice,
Tmem151a
was predominantly expressed in glutamatergic excitatory neurons and oligodendroglia, with lower expression in γ‐aminobutyric acidergic neurons and minimal expression in astrocytes and microglia.
Tmem151a
‐knockout mice exhibited heightened susceptibility to both PTZ‐ and electrostimulation‐induced seizures, along with accelerated epileptogenesis in a hippocampal kindling model. Conditional deletion of
Tmem151a
in forebrain excitatory neurons, but not in oligodendrocytes, similarly promoted epileptogenesis. Conversely, AAV‐mediated overexpression of
TMEM151A
in
Emx1
‐positive cell populations effectively suppressed seizure progression during hippocampal kindling.



Significance

Cell type‐specific knockout and overexpression experiments reveal that
TMEM151A
in forebrain excitatory neurons functions as a key regulator of seizure susceptibility. These results identify
TMEM151A
as a critical molecular determinant of neuronal network excitability and a potential therapeutic target for epilepsy.