Memory encoding and retrieval by retrosplenial parvalbumin interneurons are impaired in Alzheimer’s disease model mice

Memory deficits in Alzheimer's disease (AD) show a strong link with GABAergic interneuron dysfunctions.1Chung H. Park K. Jang H.J. Kohl M.M. Kwag J. Dissociation of somatostatin and parvalbumin interneurons circuit dysfunctions underlying hippocampal theta and gamma oscillations impaired by amyloid beta oligomers in vivo.Brain Struct. Funct. 2020; 225: 935-954https://www.ncbi.nlm.nih.gov/pubmed/32107637Crossref PubMed Scopus (32) Google Scholar,2Park K. Lee J. Jang H.J. Richards B.A. Kohl M.M. Kwag J. Optogenetic activation of parvalbumin and somatostatin interneurons selectively restores theta-nested gamma oscillations and oscillation-induced spike timing-dependent long-term potentiation impaired by amyloid beta oligomers.BMC Biol. 2020; 187https://www.ncbi.nlm.nih.gov/pubmed/31937327Crossref Scopus (41) Google Scholar,3Xu Y. Zhao M. Han Y. Zhang H. GABAergic inhibitory interneuron deficits in Alzheimer's disease: implications for treatment.Front. Neurosci. 2020; 14660https://www.ncbi.nlm.nih.gov/pubmed/32714136Crossref Scopus (88) Google Scholar,4Petrache A.L. Rajulawalla A. Shi A. Wetzel A. Saito T. Saido T.C. Harvey K. Ali A.B. Aberrant excitatory-inhibitory synaptic mechanisms in entorhinal cortex microcircuits during the pathogenesis of Alzheimer's disease.Cereb. Cortex. 2019; 29: 1834-1850https://www.ncbi.nlm.nih.gov/pubmed/30766992Crossref PubMed Scopus (1) Google Scholar,5Shi A. Petrache A.L. Shi J. Ali A.B. Preserved calretinin interneurons in an app model of Alzheimer's disease disrupt hippocampal inhibition via upregulated P2Y1 purinoreceptors.Cereb. Cortex. 2020; 30: 1272-1290https://www.ncbi.nlm.nih.gov/pubmed/31407772Crossref PubMed Scopus (10) Google Scholar,6Palop J.J. Chin J. Roberson E.D. Wang J. Thwin M.T. Bien-Ly N. Yoo J. Ho K.O. Yu G.Q. Kreitzer A. et al.Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease.Neuron. 2007; 55: 697-711https://www.ncbi.nlm.nih.gov/pubmed/17785178Abstract Full Text Full Text PDF PubMed Scopus (1207) Google Scholar,7Alberdi E. Sánchez-Gómez M.V. Cavaliere F. Pérez-Samartín A. Zugaza J.L. Trullas R. Domercq M. Matute C. Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors.Cell Calcium. 2010; 47: 264-272https://www.ncbi.nlm.nih.gov/pubmed/20061018Crossref PubMed Scopus (291) Google Scholar The ensemble dynamics of GABAergic interneurons represent memory encoding and retrieval,8Cummings K.A. Clem R.L. Prefrontal somatostatin interneurons encode fear memory.Nat. Neurosci. 2020; 23: 61-74https://www.ncbi.nlm.nih.gov/pubmed/31844314Crossref PubMed Scopus (84) Google Scholar,9Barron H.C. Vogels T.P. Behrens T.E. Ramaswami M. Inhibitory engrams in perception and memory.Proc. Natl. Acad. Sci. USA. 2017; 114: 6666-6674https://www.ncbi.nlm.nih.gov/pubmed/28611219Crossref PubMed Scopus (75) Google Scholar,10Courtin J. Karalis N. Gonzalez-Campo C. Wurtz H. Herry C. Persistence of amygdala gamma oscillations during extinction learning predicts spontaneous fear recovery.Neurobiol. Learn. Mem. 2014; 113: 82-89https://www.ncbi.nlm.nih.gov/pubmed/24091205Crossref PubMed Scopus (0) Google Scholar,11Lovett-Barron M. Kaifosh P. Kheirbek M.A. Danielson N. Zaremba J.D. Reardon T.R. Turi G.F. Hen R. Zemelman B.V. Losonczy A. Dendritic inhibition in the hippocampus supports fear learning.Science. 2014; 343: 857-863https://www.ncbi.nlm.nih.gov/pubmed/24558155Crossref PubMed Scopus (325) Google Scholar,12Wolff S.B. Gründemann J. Tovote P. Krabbe S. Jacobson G.A. Müller C. Herry C. Ehrlich I. Friedrich R.W. Letzkus J.J. et al.Amygdala interneuron subtypes control fear learning through disinhibition.Nature. 2014; 509: 453-458https://www.ncbi.nlm.nih.gov/pubmed/24814341Crossref PubMed Scopus (348) Google Scholar but how GABAergic interneuron dysfunction affects inhibitory ensemble dynamics in AD is unknown. As the retrosplenial cortex (RSC) is critical for episodic memory13Vann S.D. Aggleton J.P. Maguire E.A. What does the retrosplenial cortex do?.Nat. Rev. Neurosci. 2009; 10: 792-802https://www.ncbi.nlm.nih.gov/pubmed/19812579Crossref PubMed Scopus (969) Google Scholar,14de Sousa A.F. Cowansage K.K. Zutshi I. Cardozo L.M. Yoo E.J. Leutgeb S. Mayford M. Optogenetic reactivation of memory ensembles in the retrosplenial cortex induces systems consolidation.Proc. Natl. Acad. Sci. USA. 2019; 116: 8576-8581https://www.ncbi.nlm.nih.gov/pubmed/30877252Crossref PubMed Scopus (72) Google Scholar,15Cowansage K.K. Shuman T. Dillingham B.C. Chang A. Golshani P. Mayford M. Direct reactivation of a coherent neocortical memory of context.Neuron. 2014; 84: 432-441https://www.ncbi.nlm.nih.gov/pubmed/25308330Abstract Full Text Full Text PDF PubMed Google Scholar,16Opalka A.N. Wang D.V. Hippocampal efferents to retrosplenial cortex and lateral septum are required for memory acquisition.Learn. Mem. 2020; 27: 310-318https://www.ncbi.nlm.nih.gov/pubmed/32669386Crossref PubMed Google Scholar and is affected by β-amyloid accumulation in early AD,17Talwar P. Kushwaha S. Chaturvedi M. Mahajan V. Systematic review of different neuroimaging correlates in mild cognitive impairment and Alzheimer's disease.Clin. Neuroradiol. 2021; 31: 953-967https://www.ncbi.nlm.nih.gov/pubmed/34297137Crossref PubMed Scopus (35) Google Scholar,18Poirier G.L. Amin E. Good M.A. Aggleton J.P. Early-onset dysfunction of retrosplenial cortex precedes overt amyloid plaque formation in Tg2576 mice.Neuroscience. 2011; 174: 71-83https://www.ncbi.nlm.nih.gov/pubmed/21093545Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,19Minoshima S. Giordani B. Berent S. Frey K.A. Foster N.L. Kuhl D.E. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease.Ann. Neurol. 1997; 42: 85-94https://www.ncbi.nlm.nih.gov/pubmed/9225689Crossref PubMed Scopus (1487) Google Scholar,20Villain N. Desgranges B. Viader F. de la Sayette V. Mézenge F. Landeau B. Baron J.C. Eustache F. Chételat G. Relationships between hippocampal atrophy, white matter disruption, and gray matter hypometabolism in Alzheimer's disease.J. Neurosci. 2008; 28: 6174-6181https://www.ncbi.nlm.nih.gov/pubmed/18550759Crossref PubMed Scopus (305) Google Scholar,21Kim D.H. Kim H.A. Han Y.S. Jeon W.K. Han J.S. Recognition memory impairments and amyloid-beta deposition of the retrosplenial cortex at the early stage of 5XFAD mice.Physiol. Behav. 2020; 222112891https://www.ncbi.nlm.nih.gov/pubmed/32442584Crossref PubMed Scopus (9) Google Scholar we address this question by performing Ca2+ imaging in RSC parvalbumin (PV)-expressing interneurons during a contextual fear memory task in healthy control mice and the 5XFAD mouse model of AD. We found that populations of PV interneurons responsive to aversive electric foot shocks during contextual fear conditioning (shock-responsive) significantly decreased in the 5XFAD mice, indicating dysfunctions in the recruitment of memory-encoding PV interneurons. In the control mice, ensemble activities of shock-responsive PV interneurons were selectively upregulated during the freezing epoch of the contextual fear memory retrieval, manifested by synaptic potentiation of PV interneuron-mediated inhibition. However, such changes in ensemble dynamics during memory retrieval and synaptic plasticity were both absent in the 5XFAD mice. Optogenetic silencing of PV interneurons during contextual fear conditioning in the control mice mimicked the memory deficits in the 5XFAD mice, while optogenetic activation of PV interneurons in the 5XFAD mice restored memory retrieval. These results demonstrate the critical roles of contextual fear memory-encoding PV interneurons for memory retrieval. Furthermore, synaptic dysfunction of PV interneurons may disrupt the recruitment of PV interneurons and their ensemble dynamics underlying contextual fear memory retrieval, subsequently leading to memory deficits in AD.