Related Experiment Video
Updated: Jan 14, 2026
A Behavioral Screen for Heat-Induced Seizures in Mouse Models of Epilepsy
Published on: July 12, 2021
Altered synaptic functions in a humanized mouse model of down syndrome (TcMAC21): Implications for seizure
Li-Rong Shao1, Carl E Stafstrom1
1Division of Pediatric Neurology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Insights
Children with Down syndrome (DS) have higher seizure risks. This study reveals altered brain cell communication in a DS mouse model, identifying potential causes for increased seizure susceptibility in DS patients.
Area of Science:
- Neuroscience
- Genetics
- Pathophysiology
Background:
- Children with Down syndrome (DS) exhibit an elevated risk for seizures, such as infantile spasms and tonic-clonic seizures.
- The underlying mechanisms contributing to this increased seizure susceptibility in DS remain poorly understood.
- A novel humanized mouse model of DS (TcMAC21) displays increased infantile spasms and a heightened neocortical excitation-to-inhibition ratio.
Purpose of the Study:
- To investigate the pathophysiology of Down syndrome (DS) related to seizure susceptibility.
- To examine kainic acid receptor (KAR)-mediated excitation, GABAAR and GABABR-mediated inhibition, and synaptojanin 1 (SYNJ1) function in a DS mouse model.
- To determine if triplication of genes encoding KAR, GABABR, and SYNJ1 contributes to altered neuronal function in DS.
Main Methods:
- Whole-cell patch-clamp recordings were performed on layer V neocortical neurons from TcMAC21 mice and control euploid mice.
- The study assessed responses to kainic acid (KA) application to evaluate KAR-mediated excitation.
- Inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) were analyzed to assess GABAergic inhibition and synaptic vesicle dynamics.
Main Results:
- TcMAC21 neurons exhibited significantly larger currents in response to KA compared to control neurons, indicating enhanced KAR-mediated excitation.
- GABAAR-mediated spontaneous IPSCs were less frequent in TcMAC21 neurons, suggesting altered inhibitory neurotransmission.
- Excitatory postsynaptic currents (EPSCs) showed slower decay in TcMAC21 neurons, indicative of enhanced synaptic vesicle trafficking and reduced transmitter depletion.
Conclusions:
- This study provides the first physiological evidence for gain-of-function in KAR and SYNJ1, alongside altered GABA-mediated synaptic function, in the TcMAC21 mouse model of DS.
- These findings suggest that altered synaptic function, including enhanced excitation and modified inhibition, may underlie the increased seizure susceptibility observed in Down syndrome.
- The identified mechanisms offer potential targets for therapeutic interventions aimed at reducing seizures in individuals with DS.
Abstract:
It is not understood why children with Down syndrome (DS, trisomy of chromosome 21) have an increased risk of seizures, including infantile spasms and tonic-clonic seizures. Using a novel humanized mouse model of DS (TcMAC21), we recently showed that TcMAC21 mice express an increased propensity to infantile spasms and demonstrate an increased neocortical synaptic excitation-to-inhibition ratio. To understand the pathophysiology of DS that may predispose animals to increased seizure susceptibility, we investigated 1) kainic-acid receptor (KAR)-mediated excitation, 2) gamma-aminobutyric acid receptors A and B (GABAAR and GABABR)-mediated inhibition, and 3) synaptojanin 1 (SYNJ1) function in TcMAC21 mice, as genes encoding KAR, GABABR and SYNJ1 are among those triplicated in DS. Layer V neocortical neurons were recorded using whole-cell patch-clamp recordings to test KAR, GABAAR, GABABR, and SYNJ functions. TcMAC21 neurons responded to focal KA application with significantly larger currents than control euploid neurons. GABAAR-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) were less frequent in TcMAC21 than in euploid neurons while sIPSC amplitudes remained unchanged. Bath application of a GABABR agonist, baclofen, caused similar hyperpolarization in TcMAC21 and euploid neurons. During repetitive synaptic stimulation, excitatory postsynaptic currents (EPSCs) in TcMAC21 neurons decayed slower and to a lesser extent than control euploid neurons, indicating less transmitter depletion (i.e., enhanced synaptic vesicle trafficking). These data provide the first physiological evidence for gain-of-function of KAR and SYNJ1, and altered GABA-mediated synaptic function in TcMAC21 mice, and may represent some important DS-specific mechanisms of seizure pathogenesis.
