Related Experiment Video
Updated: Jul 4, 2026
Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
N-methyl-D-aspartate receptor subunit dysfunction at hippocampal glutamatergic synapses in an animal model of
V Jensen1, J E Rinholm, T J Johansen
1Molecular Neurobiology Research Group, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Insights
Altered synaptic transmission in the hippocampus may underlie attention-deficit/hyperactivity disorder (ADHD) symptoms. Spontaneously hypertensive rats (SHRs), an ADHD model, show impaired N-methyl-D-aspartate receptor (NMDAR) function, suggesting a potential cellular mechanism for ADHD.
Area of Science:
- Neuroscience
- Cellular Biology
- Behavioral Science
Background:
- Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by hyperactivity, impulsivity, and attention deficits.
- The spontaneously hypertensive rat (SHR) is a validated animal model for ADHD, exhibiting similar behavioral traits.
- N-methyl-D-aspartate receptors (NMDARs) are crucial for synaptic plasticity and learning in the central nervous system (CNS).
Purpose of the Study:
- To investigate potential synaptic abnormalities in glutamatergic transmission within the hippocampus of SHRs compared to control Wistar Kyoto rats (WKY).
- To explore the role of NMDAR subunits, particularly NR2B, in the altered synaptic function observed in the ADHD model.
Main Methods:
- Electrophysiological recordings of hippocampal CA3-to-CA1 synapses in SHR and WKY rats.
- Assessment of synaptic transmission, short-term plasticity, and long-term potentiation (LTP).
- Pharmacological manipulation using an NR2B-specific NMDAR blocker (CP-101,606) to probe receptor function.
- Quantitative immunofluorescence and electron microscopy to analyze NMDAR subunit expression.
Main Results:
- SHRs exhibited reduced basal synaptic transmission at hippocampal CA3-to-CA1 synapses compared to WKY controls.
- While short-term plasticity and LTP magnitude were similar, LTP in SHRs was significantly impaired by an NR2B-specific antagonist, indicating a functional NR2B predominance.
- No significant differences in the expression levels of major NMDAR subunits (NR1, NR2A, NR2B) were detected between SHR and WKY rats.
Conclusions:
- Functional impairments in glutamatergic synaptic transmission, specifically involving NMDARs, may contribute to the behavioral alterations observed in SHRs.
- The findings suggest that an altered balance or function of NMDAR subunits, particularly NR2B, could be a cellular mechanism underlying ADHD.
- This research provides insights into the neurobiological underpinnings of ADHD and highlights potential targets for therapeutic interventions.
Abstract:
Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioural disorder among children. ADHD children are hyperactive, impulsive and have problems with sustained attention. These cardinal features are also present in the best validated animal model of ADHD, the spontaneously hypertensive rat (SHR), which is derived from the Wistar Kyoto rat (WKY). Current theories of ADHD relate symptom development to factors that alter learning. N-methyl-D-aspartate receptor (NMDAR) dependent long term changes in synaptic efficacy in the mammalian CNS are thought to represent underlying cellular mechanisms for some forms of learning. We therefore hypothesized that synaptic abnormality in excitatory, glutamatergic synaptic transmission might contribute to the altered behavior in SHRs. We studied physiological and anatomical aspects of hippocampal CA3-to-CA1 synapses in age-matched SHR and WKY (controls). Electrophysiological analysis of these synapses showed reduced synaptic transmission (reduced field excitatory postsynaptic potential for a defined fiber volley size) in SHR, whereas short-term forms of synaptic plasticity, like paired-pulse facilitation, frequency facilitation, and delayed response enhancement were comparable in the two genotypes, and long-term potentiation (LTP) of synaptic transmission was of similar magnitude. However, LTP in SHR was significantly reduced (by 50%) by the NR2B specific blocker CP-101,606 (10 microM), whereas the blocker had no effect on LTP magnitude in the control rats. This indicates that the SHR has a functional predominance of NR2B, a feature characteristic of early developmental stages in these synapses. Quantitative immunofluorescence and electron microscopic postembedding immunogold cytochemistry of the three major NMDAR subunits (NR1, NR2A; and NR2B) in stratum radiatum spine synapses revealed no differences between SHR and WKY. The results indicate that functional impairments in glutamatergic synaptic transmission may be one of the underlying mechanisms leading to the abnormal behavior in SHR, and possibly in human ADHD.
