Research ArticleCA1 Spike Timing is Impaired in the 129S Inbred Strain During Cognitive Tasks
Introduction
The hippocampus is the brain region responsible for the processing of instantaneous memory during active recollection (Cho et al., 2012, Peyrache et al., 2012, Godsil et al., 2013, Li et al., 2015, Terada et al., 2017). In the CA1, excitatory synapses are formed on the dendritic spines of pyramidal (pyr) cells, and their plasticity is required for memory formation and retrieval (Penzes et al., 2011, Lai and Ip, 2013, Bosch et al., 2014, Phillips and Pozzo-Miller, 2015, Stein et al., 2015, Chazeau and Giannone, 2016, Hlushchenko et al., 2016, Nakahata and Yasuda, 2018, Penny and Gold, 2018). Therefore, genetic mutations or factors (environmental and chemical) that lead to spine dysgenesis in the CA1 produce significant cognitive symptoms that are associated with several developmental neuropsychiatric and degenerative neurological disorders.
The 129S and C57BL/6 mouse strains are among the most commonly used inbred strains in neuroscience research. Several transgenic mouse lines outbred from these parent strains are used to study synaptic plasticity, cognition, and neural circuits in the hippocampus-cortical circuits (among other circuits). Although these two strains have distinct genotypes and phenotypes, the 129S strain carries mutations that have profound effects on synaptic structure, plasticity, and cognitive performance. Notably, spontaneous mutation of the disrupted in schizophrenia 1 (Disc1) gene—which encodes DISC1, a structural protein at the excitatory postsynaptic density—results in behavioral phenotypes that recapitulate human schizophrenia and depression symptoms. In contrast, C57BL/6 mice carry the wild-type Disc1 gene and have typical (wild-type) behavioral phenotypes.
Spontaneous mutation of the Disc1 gene in 129S mice or engineered Disc1 knockout in the C57BL/6 strain (B6:Disc1 mut) truncates the primary structure of the DISC1 protein, thus significantly impairing excitatory ionotropic and metabotropic glutamate receptor scaffolding at the postsynaptic density in the cognitive centers (Koike et al., 2006, Wang et al., 2011, Wexler and Geschwind, 2011, Zheng et al., 2011, Gomez-Sintes et al., 2014, Tomoda et al., 2016, Tropea et al., 2016, Malavasi et al., 2018, Teng et al., 2018, Tropea et al., 2018). Therefore, Disc1 innate mutation in the 129S strain or induced mutation in B6 outbred strains (Disc1 knock-in, knockdown, L100P) leads to a progressive loss of excitation and spine dysgenesis in the cognitive centers (Koike et al., 2006, Kvajo et al., 2008, Lee et al., 2011, Wu et al., 2013, Gomez-Sintes et al., 2014, Shao et al., 2017, Malavasi et al., 2018).
Although Disc1 mutation primarily affects excitatory synapses, evidence suggests that the connectivity and firing rate of inhibitory γ-aminobutyric acid (GABA) neurons are influenced by abnormal DISC1 protein signaling. Genetic ablation of the Disc1 gene in B6 mice leads to mossy fiber axonal mistargeting in the CA1, impaired GABAergic signaling, diminished counts of fast-spiking interneurons, and impaired inhibitory postsynaptic current in the hippocampus (Mesbah-Oskui et al., 2015, Sauer et al., 2015). Because of the broad effects of DISC1 protein on excitatory and inhibitory synaptic activity, various types of Disc1 loss of function have been associated with the dysregulation of local hippocampal excitation, place cell function, and other related cognitive processes. Specifically, decreased resolution of the place field of CA1 place cells, suppressed hippocampal theta power, and erroneous gamma oscillations have been identified in other Disc1 mutants but not the 129S strain (Mesbah-Oskui et al., 2015, Sauer et al., 2015). Together, the dysregulation of hippocampal (pyramidal) place cell firing and brain oscillations indicate a possible change in pyramidal cell activation of interneurons in CA1 cognitive processes (Tiesinga et al., 2001, Scheffer-Teixeira and Tort, 2016, Rebollo et al., 2018, Brown et al., 2020).
Although the 129S inbred strain (with spontaneous Disc1 mutation) and outbred B6 Disc1 mutant strains show similar behavioral/synaptic phenotypes, previous studies on hippocampal function have focused on outbred B6 Disc1 mutants. This research focus has created a major gap in the interpretation of neural circuit and computational outcomes of studies involving 129S mice and associated outbred strains (Clapcote and Roder, 2006, Gomez-Sintes et al., 2014). The current study provides evidence of the dysregulation of putative pyr cell firing and excitation-driven interneuron (int) activity in the CA1 in freely behaving 129S mice. Suppression of the putative pyramidal firing rate occurred across the intervals of hippocampal-dependent spatial exploration tasks and cortex-linked executive tasks (object exploration and sociability tasks). The mean firing rates of putative pyr cells in 129S CA1 ensembles were markedly lower than those of C57BL/6 pyr cells in similar tasks. Ultimately, analysis of pyr cell-interneuron pairs in 129S and C57BL/6 CA1 revealed a lower fidelity of spike timing for 129S putative pairs. These network changes were accompanied by lower exploratory propensity and sociocognitive decline in the 129S inbred strain.
Section snippets
Experimental animals
C57BL/6 (JAX:000664) and 129S (JAX:002448) breeding pairs were acquired from Jackson Laboratories (Bar Harbor, ME, United States). Mice were housed in a temperature-controlled environment at 22 ± 1 °C with alternating 12-hour light and dark cycles. Food and water were provided ad libitum. Mice without implants were housed in groups of five per cage. Animals with neural implants were housed individually to prevent damage to the neural probes. Occasionally (two or three times per week), the
Experimental intervals for CA1 recording in freely behaving mice
The putative neuron firing rate was determined in two ways for each behavioral task. First, a change in firing rate (ΔFR, spikes/sec) was determined for putative neurons during the exploratory behavior associated with each task. Second, task-specific events such as object or social contact were used as references for determining the mean FR (Hz) of putative units. A 300-sec task duration is standard in rodent cognitive-behavioral tests (Kaidanovich-Beilin et al., 2011, Wolf et al., 2016, Brown
Discussion
129S and B6 mice are among the most commonly used inbred strains in neuroscience research. Several transgenic lines and outbred strains have been developed from these individual strains or a combination of 129S and B6 lines. Generally, the 129S inbred lines bear significant mutations that could impair neural and cognitive function. A notable mutation in the 129S strain alters the Disc1 gene and leads to the truncation of the DISC1 primary protein structure. Among other defects, the loss of Disc1
Author contributions
OOM, AS, APA, and CCL designed the experiments and performed the recording procedures. OOM, AS, AT, and APA analyzed the results. OOM, CCL, and AT prepared the manuscript. OOM and CCL verified the manuscript.
Acknowledgments
This work was funded by a CBS Bridging Grant (2020–2021) awarded to OOM. NIH grants R03MH104851, R03AG052120, R03AG056956, and R03NS109682 were awarded to CCL. Also, IBRO-ARC Fellowship awarded to APA.
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