The Animal Model Perspective

Transcription

1 May 6 th 2011, CL Davis Foundation, Novartis Pharma, East Hanover, NJ The Animal Model Perspective A Heuristic Approach for Studying Mechanisms Underlying the Development of Psychiatric Disorders Kuei Y. Tseng, MD, PhD Assistant Professor Cellular & Molecular Pharmacology RFUMS/The Chicago Medical School North Chicago, Illinois USA

2 THC Modified from Tseng, Chambers & Lipska, BBR 2009 (review)

3 Modified from Animal Models of Schizophrenia (April 9, 2009) Schizophrenia Research Forum - Developmental l Preparations + Fetal Irradiation (non-human primates) + Prenatal & Neonatal Immune Challenge (human influenza virus, LPS, Polyl-C, borna disease virus) + Prenatal Stress + Prenatal Vitamin D Insufficiency + Placental Insufficiency/Birth Insults + Antimitotic Agent MAM or AraC + Neonatal Lesions (amygdala, ventral hippocampus, prefrontal cortex) + Social Isolation Rearing + Maternal Deprivation on PD 9 (i.e., 24 Hs) + Maternal Malnutrition

4 Modified from Animal Models of Schizophrenia (April 9, 2009) Schizophrenia Research Forum - Drug-induced Preparations + NMDA receptor antagonism (MK801, PCP, Ketamine) +Drug-induced disruption of glutamate transporter + Chronic methamphetamine treatment + Basolateral amygdala picrotoxin infusion + Drug-induced Glutathione Depletion (oxidative stress) + Disinhibition of the ventral hippocampus + Neonatal EGF treatment t t

5 Modified from Animal Models of Schizophrenia (April 9, 2009) Schizophrenia Research Forum - Genetic Preparations (selected from over 60 models) + Adenosine Kinase Transgenic Mice + Alpha-CaMKII KO + Beta-arrestin 2 KO + Calcineurin A-gamma KO + Cannabinoid Receptor 1 (CB1) KO + Catecholamine O-methyl transferase (COMT) KO + Complexin I and II KO + DISC1 KO, DISC-truncated, Inducible Mutant hdisc1 + Dopamine Transporter KO + Dysbindin-1, Sandy (sdy) Mouse + Heterozygous Reeler Mouse + Neuregulin 1 Hypomorph (Transmembrane Domain) + Transient D2 Receptor Overexpression

6 Modified from Tseng, Chambers & Lipska, BBR 2009 (review) Developmental Trajectories of Neural Circuits & Psychiatric Syndromes genetic predisposition developmental changes synaptic alterations functional changes in neuronal circuits Prefrontal Cortex Cingulate Cortex Orbitofrontal Cortex Environmental Factors Dopamine Noradrenaline Serotonin Histamine Hippocampus Amygdala Thalamus Basal Ganglia

7 O'Donnell P Schizophr Bull 2011;37: Ad l t O t f C ti l Di i hibiti i S hi h i Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models

8 Gap in knowledge

9 Susan L. Andersen (2003) Neurosci Biobehav Rev 2003, 27(1-2):3-18 2):3 18 Trajectories of Brain Development: point of vulnerability or window of opportunity? 1. Synapses within most mammalian brain regions are overproduced and eliminated by as much as 50% during two phases of life: (a) immediately before birth (b) during the periadolescent transition to adulthood 2. The brain becomes wired to match the needs of the environment, in particular during critical periods of development 3. Changes induced by both positive and negative factors during the periadolescent transition period can significantly imprint/alter the final trajectory of the adult brain

10 Modified from Tseng 2007, Springer Dopamine regulation of PFC excitability increases during the periadolescent transition to adulthood

11 Increased vulnerability to drug addiction during the periadolescent transition period 1. Drug addiction is a chronic disorder characterized by compulsive drug craving, seeking, and use that persist despite severe adverse consequences 2. Most experimentation with drugs occurs during adolescence and early adulthood (Compton et al 2004; Spear 2000; SAMHSA*) 3. Risk for drug addiction is a four-fold higher if drug exposure takes place during adolescence (12 14 years of age) compared to exposure during young adulthood (21 25 years of age) (O Brien & Anthony 2005) 4. However, very little is known about the neurodevelopmental processes that mediate this vulnerability *Substance Abuse and Mental Health Services Administration:

12 Our Goal To determine how repeated drug exposure (e.g., cocaine) during the adolescence affects the frontal cortical circuits in adulthood Modified from Tseng et al 2009, BBR (review article)

13 Experimental Procedure Male Sprague Dawley rats Twoage groups: adolescent (PD35) and adult (PD75) rats Single daily injection of cocaine or saline for 5 consecutive days (home cage) Doses: 15 and 25 mg/kg i.p. Endpoint: 3 days and 3 weeks after the last injection Cortical activity: cytochrome oxidase (CO-I) histochemistry

14 Results 1: overall changes

15 Prefrontal Hyperactivity: lack of inhibition?

16 Results 2: developmental upregulation of PV + /FS interneurons Results 2: developmental upregulation of PV /FS interneurons in the medial prefrontal cortex

17 Results 3: downregulation of PV-ir in the prefrontal cortex

18 Modified from Tseng, Chambers & Lipska, BBR 2009 (review)

19 Results 4: facilitation of the hippocampal-prefrontal cortex synaptic transmission

20 Results 5: shift from prefrontal LTD to LTP in response to hippocampal HFS (4 trains/50pulses/100hz/15s)

21 Summary & Conclusions overall inhibition frontal output of cortical output t PV (FSI) inhibition

22 Regulation of PV-ir in cortical circuits 1. Downregulation of PV immunoreactivity: a) loss of PV interneurons b) loss of the PV phenotype c) loss of PV dendritic complexity d) loss of PV interneuron synapses onto pyramidal cells 2. NR2A-containing NMDAR are required to maintain PV-ir and GAD67 phenotype in cultured interneurons (Kinney et al 2006) 3. Ketamine-induced loss of fast-spiking/pv + interneuron phenotype is mediated by NADPH-oxidase (Behrens et al 2007) 4. PV + interneurons are susceptible to redox dysregulation in the developing cortex (Do et al 2009)

23 Working Hypothesis (cellular/synaptic) activation blockade

24 Developmental regulation of PV interneurons in the prefrontal cortex: role of NMDA & CB1 receptors

25 Working Hypothesis (network/circuit)? prefrontal output hyperactivity

26 THC Modified from Tseng, Chambers & Lipska, BBR 2009 (review)

27 Acknowledgments Laboratory of Cellular & Synaptic Plasticity Lab Members Adriana Caballero, PhD (research associate) Eden Flores-Barrera, PhD (research associate) Daryn K. Cass (research assistant/lab manager) Daniel Thomases (graduate student) Former Lab Members Li-Jun Heng, MD (research associate) Shannon Blume (research assistant) Gregorio Galiñanes, PhD (fellow) Andrui Nazarian, MS (MD student) Dylan Burdette (graduate student) Andrew Schreyer (graduate student) Natalie Simak (lab technician) Pascal Accoh (lab technician) Sergio Lew, PhD (postdoctoral fellow, Argentina) Collaborators Dr. West (Neuroscience, CMS, Rosalind Franklin Univ) Dr. Wolf (Neuroscience, CMS, Rosalind Franklin Univ) Dr. Reynolds (Univ Otago, New Zealand) Current Funding NIMH (R01 MH086507, PI) NIDA (R01 DA009621, Co-I) Parkinson Research Institute Innovation Grant (PI) Rosalind Franklin University Start-up Funds