Archival Report| Volume 88, ISSUE 9, P710-718, November 01, 2020

Modular, Circuit-Based Interventions Rescue Hippocampal-Dependent Social and Spatial Memory in a 22q11.2 Deletion Syndrome Mouse Model

  • Julia B. Kahn
    Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Search for articles by this author
  • Russell G. Port
    Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania
    Search for articles by this author
  • Stewart A. Anderson
    Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania
    Search for articles by this author
  • Douglas A. Coulter
    Address correspondence to Douglas A. Coulter, Ph.D.
    Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania
    Search for articles by this author



      22q11.2 deletion syndrome (22qDS) manifests with myriad symptoms, including multiple neuropsychiatric disorders. Complications associated with the polygenic haploinsufficiency make 22qDS symptoms particularly difficult to manage with traditional therapeutic approaches. However, the varying mechanistic consequences often culminate to generate inappropriate regulation of neuronal circuit activity. We explored whether managing this aberrant activity in adults could be a therapeutically beneficial strategy.


      To assess and dissect hippocampal circuit function, we performed functional imaging in acute slices and targeted eloquent circuits (specific subcircuits tied to specific behavioral tasks) to provide relevant behavioral outputs. For example, the ventral and dorsal CA1 regions critically support social and spatial discrimination, respectively. We focally introduced chemogenetic constructs in 34 control and 24 22qDS model mice via adeno-associated viral vectors, driven by excitatory neuron-specific promoter elements, to manipulate circuit recruitment in an on-demand fashion.


      22qDS model mice exhibited CA1 excitatory ensemble hyperexcitability and concomitant behavioral deficits in both social and spatial memory. Remarkably, acute chemogenetic inhibition of pyramidal cells successfully corrected memory deficits and did so in a regionally specific manner: ventrally targeted constructs rescued only social behavior, while those expressed dorsally selectively affected spatial memory. Additionally, manipulating activity in control mice could recapitulate the memory deficits in a regionally specific manner.


      These data suggest that retuning activity dysregulation can rescue function in disease-altered circuits, even in the face of a polygenetic haploinsufficiency with a strong developmental component. Targeting circuit excitability in a focal, modular manner may prove to be an effective therapeutic for treatment-resistant symptoms of mental illness.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Van L.
        • Boot E.
        • Bassett A.S.
        Update on the 22q11.2 deletion syndrome and its relevance to schizophrenia.
        Curr Opin Psychiatry. 2017; 30: 191-196
        • Green T.
        • Gothelf D.
        • Glaser B.
        • Debbane M.
        • Frisch A.
        • Kotler M.
        • et al.
        Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome.
        J Am Acad Child Adolesc Psychiatry. 2009; 48: 1060-1068
        • Gothelf D.
        • Presburger G.
        • Zohar A.H.
        • Burg M.
        • Nahmani A.
        • Frydman M.
        • et al.
        Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome.
        Am J Med Genet B Neuropsychiatr Genet. 2004; 126B: 99-105
        • Schneider M.
        • Schaer M.
        • Mutlu A.K.
        • Menghetti S.
        • Glaser B.
        • Debbané M.
        • Eliez S.
        Clinical and cognitive risk factors for psychotic symptoms in 22q11.2 deletion syndrome: a transversal and longitudinal approach.
        Eur Child Adolesc Psychiatry. 2014; 23: 425-436
        • Niklasson L.
        • Rasmussen P.
        • Óskarsdóttir S.
        • Gillberg C.
        Autism, ADHD, mental retardation and behavior problems in 100 individuals with 22q11 deletion syndrome.
        Res Dev Disabil. 2009; 30: 763-773
        • Gur R.E.
        • Yi J.J.
        • McDonald-McGinn D.M.
        • Tang S.X.
        • Calkins M.E.
        • Whinna D.
        • et al.
        Neurocognitive development in 22q11.2 deletion syndrome: Comparison with youth having developmental delay and medical comorbidities.
        Mol Psychiatry. 2014; 19: 1205-1211
        • Van Den Heuvel E.
        • Jonkers E.
        • Rombouts E.
        • Manders E.
        • Zink I.
        • Swillen A.
        Exploratory study on cognitive abilities and social responsiveness in children with 22q11.2 deletion syndrome (22q11DS) and children with idiopathic intellectual disability (IID).
        Res Dev Disabil. 2018; 81: 89-102
        • Shashi V.
        • Veerapandiyan A.
        • Schoch K.
        • Kwapil T.
        • Keshavan M.
        • Ip E.
        • Hooper S.
        Social skills and associated psychopathology in children with chromosome 22q11.2 deletion syndrome: Implications for interventions.
        J Intellect Disabil Res. 2012; 56: 865-878
        • Campbell L.E.
        • McCabe K.L.
        • Melville J.L.
        • Strutt P.A.
        • Schall U.
        Social cognition dysfunction in adolescents with 22q11.2 deletion syndrome (velo-cardio-facial syndrome): Relationship with executive functioning and social competence/functioning.
        J Intellect Disabil Res. 2015; 59: 845-859
        • Lattanzi G.M.
        • Buzzanca A.
        • Frascarelli M.
        • Di Fabio F.
        Genetic and clinical features of social cognition in 22q11.2 deletion syndrome.
        J Neurosci Res. 2018; 96: 1631-1640
        • Mosheva M.
        • Korotkin L.
        • Gur R.E.
        • Weizman A.
        • Gothelf D.
        Effectiveness and side effects of psychopharmacotherapy in individuals with 22q11.2 deletion syndrome with comorbid psychiatric disorders: A systematic review.
        Eur Child Adolesc Psychiatry. 2020; 29: 1035-1048
        • Eaton C.B.
        • Thomas R.H.
        • Hamandi K.
        • Payne G.C.
        • Kerr M.P.
        • Linden D.E.J.
        • et al.
        Epilepsy and seizures in young people with 22q11.2 deletion syndrome: Prevalence and links with other neurodevelopmental disorders.
        Epilepsia. 2019; 60: 818-829
        • Kates W.R.
        • Miller A.M.
        • Abdulsabur N.
        • Antshel K.M.
        • Conchelos J.
        • Fremont W.
        • Roizen N.
        Temporal lobe anatomy and psychiatric symptoms in velocardiofacial syndrome (22q11.2 deletion syndrome).
        J Am Acad Child Adolesc Psychiatry. 2006; 45: 587-595
        • Flahault A.
        • Schaer M.
        • Ottet M.-C.
        • Debbané M.
        • Eliez S.
        Hippocampal volume reduction in chromosome 22q11.2 deletion syndrome (22q11.2DS): A longitudinal study of morphometry and symptomatology.
        Psychiatry Res Neuroimaging. 2012; 203: 1-5
        • Scott J.A.
        • Goodrich-Hunsaker N.
        • Kalish K.
        • Lee A.
        • Hunsaker M.R.
        • Schumann C.M.
        • et al.
        The hippocampi of children with chromosome 22q11.2 deletion syndrome have localized anterior alterations that predict severity of anxiety.
        J Psychiatry Neurosci. 2016; 41: 203-213
        • Mancini V.
        • Sandini C.
        • Padula M.C.
        • Zöller D.
        • Schneider M.
        • Schaer M.
        • Eliez S.
        Positive psychotic symptoms are associated with divergent developmental trajectories of hippocampal volume during late adolescence in patients with 22q11DS [published online ahead of print Jun 4].
        Mol Psychiatry. 2019;
        • Schleifer C.
        • Lin A.
        • Kushan L.
        • Ji J.L.
        • Yang G.
        • Bearden C.E.
        • Anticevic A.
        Dissociable disruptions in thalamic and hippocampal resting-state functional connectivity in youth with 22q11.2 deletions.
        J Neurosci. 2019; 39: 1301-1319
        • Shenton M.E.
        • Dickey C.C.
        • Frumin M.
        • McCarley R.W.
        A review of MRI findings in schizophrenia.
        Schizophr Res. 2001; 49: 1-52
        • Steen R.G.
        • Mull C.
        • Mcclure R.
        • Hamer R.M.
        • Lieberman J.A.
        Brain volume in first-episode schizophrenia.
        Br J Psychiatry. 2006; 188: 510-518
        • Samudra N.
        • Ivleva E.I.
        • Hubbard N.A.
        • Rypma B.
        • Sweeney J.A.
        • Clementz B.A.
        • et al.
        Alterations in hippocampal connectivity across the psychosis dimension.
        Psychiatry Res Neuroimaging. 2015; 233: 148-157
        • McHugo M.
        • Talati P.
        • Armstrong K.
        • Vandekar S.N.
        • Blackford J.U.
        • Woodward N.D.
        • Heckers S.
        Hyperactivity and reduced activation of anterior hippocampus in early psychosis.
        Am J Psychiatry. 2019; 176: 1030-1038
        • Talati P.
        • Rane S.
        • Kose S.
        • Blackford J.U.
        • Gore J.
        • Donahue M.J.
        • Heckers S.
        Increased hippocampal CA1 cerebral blood volume in schizophrenia.
        Neuroimage Clin. 2014; 5: 359-364
        • Rubin R.D.
        • Watson P.D.
        • Duff M.C.
        • Cohen N.J.
        The role of the hippocampus in flexible cognition and social behavior.
        Front Hum Neurosci. 2014; 8: 1-15
        • Montagrin A.
        • Saiote C.
        • Schiller D.
        The social hippocampus.
        Hippocampus. 2018; 28: 672-679
        • Meira T.
        • Leroy F.
        • Buss E.W.
        • Oliva A.
        • Park J.
        • Siegelbaum S.A.
        A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics.
        Nat Commun. 2018; 9: 4163
        • Chiang M.C.
        • Huang A.J.Y.
        • Wintzer M.E.
        • Ohshima T.
        • McHugh T.J.
        A role for CA3 in social recognition memory.
        Behav Brain Res. 2018; 354: 22-30
        • Okuyama T.
        • Kitamura T.
        • Roy D.S.
        • Itohara S.
        • Tonegawa S.
        Ventral CA1 neurons store social memory.
        Science. 2016; 353: 1536-1541
        • Phillips M.L.
        • Robinson H.A.
        • Pozzo-Miller L.
        Ventral hippocampal projections to the medial prefrontal cortex regulate social memory.
        Elife. 2019; 8: 1-32
        • Didriksen M.
        • Fejgin K.
        • Nilsson S.R.O.
        • Birknow M.R.
        • Grayton H.M.
        • Larsen P.H.
        • et al.
        Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: A study in male mice.
        J Psychiatry Neurosci. 2017; 42: 48-58
        • Kahn J.B.
        • Port R.G.
        • Yue C.
        • Takano H.
        • Coulter D.A.
        Circuit-based interventions in the dentate gyrus rescue epilepsy-associated cognitive dysfunction.
        Brain. 2019; 142: 2705-2721
        • Oliveira A.M.M.
        • Hawk J.D.
        • Abel T.
        • Havekes R.
        Post-training reversible inactivation of the hippocampus enhances novel object recognition memory.
        Learn Mem. 2010; 17: 155-160
        • Armbruster B.N.
        • Li X.
        • Pausch M.H.
        • Herlitze S.
        • Roth B.L.
        Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.
        Proc Natl Acad Sci U S A. 2007; 104: 5163-5168
        • Vardy E.
        • Robinson J.E.
        • Li C.
        • Olsen R.H.J.
        • DiBerto J.F.
        • Giguere P.M.
        • et al.
        A new DREADD facilitates the multiplexed chemogenetic interrogation of behavior.
        Neuron. 2015; 86: 936-946
        • Piskorowski R.A.
        • Nasrallah K.
        • Diamantopoulou A.
        • Mukai J.
        • Hassan S.I.
        • Siegelbaum S.A.
        • et al.
        Age-dependent specific changes in area CA2 of the hippocampus and social memory deficit in a mouse model of the 22q11.2 deletion syndrome.
        Neuron. 2016; 89: 163-176
        • Marissal T.
        • Salazar R.F.
        • Bertollini C.
        • Mutel S.
        • De Roo M.
        • Rodriguez I.
        • et al.
        Restoring wild type-like network dynamics and behaviour during adulthood in a mouse model of schizophrenia.
        Nat Neurosci. 2018; 21: 1412-1420
        • Mukherjee A.
        • Carvalho F.
        • Eliez S.
        • Caroni P.
        Long-lasting rescue of network and cognitive dysfunction in a genetic schizophrenia model.
        Cell. 2019; 178: 1387-1402.e14
        • Gomez J.L.
        • Bonaventura J.
        • Lesniak W.
        • Mathews W.B.
        • Sysa-Shah P.
        • Rodriguez L.A.
        • et al.
        Chemogenetics revealed: DREADD occupancy and activation via converted clozapine.
        Science. 2017; 357: 503-507
        • Zaremba J.D.
        • Diamantopoulou A.
        • Danielson N.B.
        • Grosmark A.D.
        • Kaifosh P.W.
        • Bowler J.C.
        • et al.
        Impaired hippocampal place cell dynamics in a mouse model of the 22q11.2 deletion.
        Nat Neurosci. 2017; 20: 1612-1623
        • Earls L.R.
        • Bayazitov I.T.
        • Fricke R.G.
        • Berry R.B.
        • Illingworth E.
        • Mittleman G.
        • Zakharenko S.S.
        Dysregulation of presynaptic calcium and synaptic plasticity in a mouse model of 22q11 deletion syndrome.
        J Neurosci. 2010; 30: 15843-15855
        • Lopez A.J.
        • Kramar E.
        • Matheos D.P.
        • White A.O.
        • Kwapis J.
        • Vogel-Ciernia A.
        • et al.
        Promoter-specific effects of DREADD modulation on hippocampal synaptic plasticity and memory formation.
        J Neurosci. 2016; 36: 3588-3599
        • Schneider M.
        • Debbané M.
        • Bassett A.S.
        • Chow E.W.C.
        • Fung W.L.A.
        • van den Bree M.B.M.
        • et al.
        Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the international consortium on brain and behavior in 22q11.2 deletion syndrome.
        Am J Psychiatry. 2014; 171: 627-639
        • Chen X.
        • Choo H.
        • Huang X.P.
        • Yang X.
        • Stone O.
        • Roth B.L.
        • Jin J.
        The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs.
        ACS Chem Neurosci. 2015; 6: 476-484
        • Thompson K.J.
        • Khajehali E.
        • Bradley S.J.
        • Navarrete J.S.
        • Huang X.P.
        • Slocum S.
        • et al.
        DREADD agonist 21 is an effective agonist for muscarinic-based DREADDs in vitro and in vivo.
        ACS Pharmacol Transl Sci. 2018; 1: 61-72
        • Bonaventura J.
        • Eldridge M.A.G.
        • Hu F.
        • Gomez J.L.
        • Sanchez-Soto M.
        • Abramyan A.M.
        • et al.
        High-potency ligands for DREADD imaging and activation in rodents and monkeys.
        Nat Commun. 2019; 10: 4627
        • Dimidschstein J.
        • Chen Q.
        • Tremblay R.
        • Rogers S.L.
        • Saldi G.-A.
        • Guo L.
        • et al.
        A viral strategy for targeting and manipulating interneurons across vertebrate species.
        Nat Neurosci. 2016; 19: 1743-1749
        • Wolff A.R.
        • Bygrave A.M.
        • Sanderson D.J.
        • Boyden E.S.
        • Bannerman D.M.
        • Kullmann D.M.
        • Kätzel D.
        Optogenetic induction of the schizophrenia-related endophenotype of ventral hippocampal hyperactivity causes rodent correlates of positive and cognitive symptoms.
        Sci Rep. 2018; 8: 12871
        • Donegan J.J.
        • Tyson J.A.
        • Branch S.Y.
        • Beckstead M.J.
        • Anderson S.A.
        • Lodge D.J.
        Stem cell-derived interneuron transplants as a treatment for schizophrenia: Preclinical validation in a rodent model.
        Mol Psychiatry. 2017; 22: 1492-1501
        • Donegan J.J.
        • Boley A.M.
        • Yamaguchi J.
        • Toney G.M.
        • Lodge D.J.
        Modulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner.
        Nat Commun. 2019; 10: 2819
        • Gilani A.I.
        • Chohan M.O.
        • Inan M.
        • Schobel S.A.
        • Chaudhury N.H.
        • Samuel P.
        • et al.
        Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition.
        Proc Natl Acad Sci U S A. 2014; 111: 7450-7455
        • Neves G.A.
        • Grace A.A.
        α7 Nicotinic receptor-modulating agents reverse the hyperdopaminergic tone in the MAM model of schizophrenia.
        Neuropsychopharmacology. 2018; 43: 1712-1720
        • Ewing S.G.
        • Grace A.A.
        Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia.
        Schizophr Res. 2013; 143: 377-383

      Linked Article

      • Circuit-Based Interventions for the Treatment of Behaviors Relevant to Schizophrenia
        Biological PsychiatryVol. 88Issue 9
        • Preview
          Aberrant hippocampal structure and function has been implicated in a variety of psychiatric disorders; however, the specific hippocampal circuits contributing to discrete symptom domains have not been extensively evaluated. The hippocampus has long been associated with the consolidation of declarative memory where dysfunction leads to amnesia (1); however, it is also intimately associated with emotion and stress responsivity where aberrant activity is associated with disorders such as schizophrenia and depression (2,3).
        • Full-Text
        • PDF