Social cognition deficits in the J20 mouse model of Alzheimer’s disease

The hippocampal CA2 subregion plays important roles in regulating social behaviors. It is required for the encoding, consolidation, and recall of social memory, and acts to promote social odor discrimination learning [1,2,3]. CA2 dysfunction has been implicated in several neuropsychiatric disorders associated with abnormal social behavior, including epilepsy, schizophrenia, and different forms of dementia. Recent studies of the Tg2576 mouse model of Alzheimer’s disease (AD) reported a decrease in inhibitory synaptic transmission and synaptic plasticity that contributes to social memory deficits [4]. Here, we explore another genetic model of AD, the J20 mouse line, to determine whether altered social memory and CA2 function are a common feature of AD mouse models.

We subjected the mice to a CA2-dependent social novelty recognition task, in which a subject mouse explores an arena containing a novel conspecific and a previously encountered conspecific confined to separate wire cup cages. Social memory is manifested by the preference of the subject to explore the novel mouse, measured as a discrimination index (DI). Male J20 mice show a significant impairment in this task, and strikingly, age-matched female J20 mice show a normal social memory behavior (two-way ANOVA, DI ~ sexgenotype*: significant main effect of sex, F(1, 52) = 4.382, P=0.0412; significant main effect of genotype, F(1, 52) = 4.474, P=0.0392; non-significant interaction between factors, F(1, 52) = 2.477, P=0.1216; Male WT vs Male J20 P=0.0497, Tukey’s multiple comparisons test). In a head-fixed odor discrimination task, J20 mice show normal learning of social odors across training sessions (linear mixed-effects model, performance ~ sessiongenotype*: significant main effect of session, β=0.033 ± 0.007, P=0.001; non-significant main effect of genotype, β=-0.096 ± 0.076, P=0.210; non-significant interaction between factors, β=0.011± 0.012, P=0.324).

To understand the mechanisms underlying the differences encountered within the J20 group, we collected the brains of the mice subjected to social behavioral tests to measure the expression of cellular markers that could be associated with their performance. So far, we have not found a correlation between social memory impairment and ΔFosB immunoreactivity, a readout of hippocampal seizure activity that has previously been correlated with deficits in spatial learning and memory [5] (Spearman’s correlation: non-significant correlation between social novelty DI and ΔFosB immunoreactivity, r_s(26) = -0.2928, P=0.1305). We are currently assessing parvalbumin interneurons and perineuronal nets in CA2 subregion.

In ex vivo electrophysiological experiments, we have so far failed to observe a significant difference in either intrinsic electrophysiological properties of CA2 pyramidal neurons (Mann-Whitney U tests, WT vs J20: U=75, P=0.6673) or in the amplitude of excitatory or inhibitory synaptic potentials evoked by electrical stimulation of the hippocampal or cortical inputs to CA2 in J20 compared to wild-type mice (respectively: U=24, P= 0.6943; U=11, P= 0.5368).

Overall, our data so far suggest that J20 mice show social memory impairment unrelated to hippocampal seizure activity, and despite normal learning of social odors and normal CA2 ex vivo function. Future experiments will explore whether the deficit in social memory is associated with altered in vivo activity of CA2 neurons in this AD mouse model.

References

1. Meira T, Leroy F, Buss EW, Oliva A, Park J, Siegelbaum SA, 2018. A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics. Nat Commun. 9(1):4163.
2. Oliva A, Fernández-Ruiz A, Leroy F, Siegelbaum SA, 2020. Hippocampal CA2 sharp-wave ripples reactivate and promote social memory. Nature. 587(7833):264-269.
3. Hassan SI, Bigler S, Siegelbaum SA, 2023. Social odor discrimination and its enhancement by associative learning in the hippocampal CA2 region. Neuron. 111(14):2232-2246.e5.
4. Rey CC, Robert V, Bouisset G, Loisy M, Lopez S, Cattaud V, Lejards C, Piskorowski RA, Rampon C, Chevaleyre V, Verret L, 2022. Altered inhibitory function in hippocampal CA2 contributes in social memory deficits in Alzheimer’s mouse model. iScience. 25(3):103895.
5. Corbett BF, You JC, Zhang X, Pyfer MS, Tosi U, Iascone DM, Petrof I, Hazra A, Fu CH, Stephens GS, Ashok AA, Aschmies S, Zhao L, Nestler EJ, Chin J, 2017. ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease. Cell Rep. 20(2):344-355.