Major theories of schizophrenia

Major theories of schizophrenia
NMDA hypofunction theory (NMDAR antagonists given to humans induce all major symptoms of the disease) Dopamine hyperfunction theory (D2 antagonists produce effective treatment of schizophrenia) Interneuron theory (postmortem tissue shows a reduction of GAD and parvalbumin in fast-spiking interneurons)

Hippocampus Thalamus reuniens mPFC Delta nRT NR2C D2 T-type Ca channel
Cognitive symptoms: deficit in signal from mPFC prevents delayed alternation working memory task Hippocampus Thalamus Corollary discharge CA1 reuniens mPFC Fast spiking interneuron Delta Previous trial nRT Gamma NR2C D2 T-type Ca channel Psychosis from delta generated by positive feedback in the hippocampus- VTA-thalamus loop. Delta jams communication through particular thalamic nuclei. VTA

Theta-gamma discrete phase code
Place A Place B Storage of 7 +/- 2 short-term memories in oscillatory subcycles. Lisman JE, Idiart MA. Science. 1995 PLACE CELLS. Autoassociative dynamics in the generation of sequences of hippocampal place cells. Pfeiffer BE, Foster DJ. Science. 2015

d= delay of feedback inhibition,
~ 5msec d= delay of feedback inhibition, tau = membrane time-constant; govern decay of IPSP A second function of gamma frequency oscillations: an E%-max winner-take-all mechanism selects which cells fire. de Almeida L, Idiart M, Lisman JE. J Neurosci. 2009

Orientation selectivity
Proc Natl Acad Sci U S A. 2012 Mar 13;109(11): Orientation selectivity and noise correlation in awake monkey area V1 are modulated by the gamma cycle. Womelsdorf T1, Lima B, Vinck M, Oostenveld R, Singer W, Neuenschwander S, Fries P.

Theta-gamma code in the hippocampus is organized by inhibition that enhances sparsity of firing
Position A Position B Local feedback inhibition Inhibition organized by medial septal nucleus

Delta frequency waves in slow wave sleep
Wake/REM EEG Delta is synchronized over all cortical regions McCarley et al, J. Neurophysiol. 1983, 50:798

Boutros NN, Arfken C, Galderisi S, Warrick J, Pratt G, Iacono W.
Schizophr Res Feb;99(1-3): Epub 2007 Dec 21. Links The status of spectral EEG abnormality as a diagnostic test for schizophrenia. Boutros NN, Arfken C, Galderisi S, Warrick J, Pratt G, Iacono W. OBJECTIVE: A literature review was conducted to ascertain whether or not EEG spectral abnormalities are consistent enough to warrant additional effort towards developing them into a clinical diagnostic test for schizophrenia. METHODS: Fifty three papers met criteria for inclusion into the review and 15 were included in a meta-analysis of the degree of significance of EEG deviations as compared to healthy controls. Studies were classified based on a 4-step approach based on guidelines for evaluating the clinical usefulness of a diagnostic test. RESULTS: Our review and meta-analysis revealed that most of the abnormalities are replicated in the expected directions with the most consistent results related to the increased preponderance of slow rhythms in schizophrenia patients This effect remained consistent in un-medicated patients. A second meta-analysis, this time of studies using MEG instead of EEG, concludes that theta/delta is elevated in temporal lobe (Siekmeier PJ, Stufflebeam SM. )

Elliot Hong L, Moran LV, Du X, O'Donnell P, Summerfelt A.
Mismatch negativity and low frequency oscillations in schizophrenia families. Elliot Hong L, Moran LV, Du X, O'Donnell P, Summerfelt A. Clin Neurophysiol. 2012 Enhanced delta is NOT seen in their first degree relatives {Clementz, 1994 ; Sponheim, 2003 ;Venables, 2009}. Even in twins discordant for schizophrenia increased delta was not observed in the healthy twin {Stassen, 1999 ;Weisbrod, 2004}.

J Pharmacokinet Biopharm. 1987 Jun;15(3):241-53.
Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. Schüttler J, Stanski DR, White PF, Trevor AJ, Horai Y, Verotta D, Sheiner LB.

***another success for the NMDA hypofunction model
Delta oscillations appear in the frontal cortical EEG in response to NMDA antagonist ***another success for the NMDA hypofunction model Buzsaki, 1988 Why does an antagonist of an excitatory amino acid stimulate oscillations?

Yuchun Zhang

Does NMDAR antagonist affect cortex by acting on the thalamus?
nRT GABA thalamic nucleus Nucleus reticularis PACEMAKER

APV induces delta frequency bursting in isolated nRT (nucleus reticular is)
Single spikes Delta frequency bursting

Blocking NMDAR hyperpolarizes neurons of thalamic reticular nucleus (nRT)

Rodolfo Llinas

Thalamocortical dysrhythmia: abnormal delta frequency oscillations in the awake state----role of resting potential and T-type Ca channels Firing mode Llinas et al, 2005, TINS, 28:325

The hyperpolarization produced by blocking NMDAR changes firing mode in the nRT

Why does NMDAR antagonist hyperpolarize nRT neurons?

Science Nov 10;246(4931):815- Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. Sah P, Hestrin S, Nicoll RA. Department of Pharmacology, University of California, San Francisco Voltage clamp recordings and noise analysis from pyramidal cells in hippocampal slices indicate that N-methyl-D-aspartate (NMDA) receptors are tonically active. On the basis of the known concentration of glutamate in the extracellular fluid, this tonic action is likely caused by the ambient glutamate level. NMDA receptors are voltage-sensitive, thus background activation of these receptors imparts a regenerative electrical property to pyramidal cells, which facilitates the coupling between dendritic excitatory synaptic input and somatic action potential discharge in these neurons.

Ambient glutamate produces partial tonic activation of NMDARs, but with NR2A and NR2B, this has no effect on resting potential because the channels are blocked by Mg. Why is thalamus different? neuro4e-fig r.jpg

NR2C is strongly expressed in the mouse thalamus (Allen Brain Atlas)

I-V curves of NMDAR in nRT cells shows weak Mg block (weak rectification) characteristic of NR2C

In the NR2C knockout mouse (Andres Buonanno), the weak rectification of the NMDAR response is eliminated

What is the localization of delta in the thalamus, cortex and hippocampus?

Hints of a special role for midline thalamic nuclei (including the nucleus reuniens)
B Castran Bruce Cohen Neuroleptics excite local interneurons in midline thalamic nuclei NMDAR antagonist produces largest cFOS signal in midline nuclei 28

Ketamine injection into the reuniens increases hippocampal delta and increases the firing rate of CA1 cells

Merck T-channel antagonist (TTA-P2) prevents the increase in delta caused by injection of Ketamine into Reuniens Ketamine injection into reuniens Ketamine injection into reuniens TTA-P2

How high-resolution basal-state functional imaging can guide the development of new pharmacotherapies for schizophrenia. Gaisler-Salomon I, Schobel SA, Small SA, Rayport S. Schizophr Bull Nov;35(6):

D2 antagonist depolarizes nRT and blocks the bursting produced by APV; this could be a basis for the efficacy of neuroleptics

Use of an in vivo model in which ketamine is injected into RE and delta is measured in the hippocampus. The increase in delta is blocked by D2 antagonist.

Is the abnormal delta frequency bursting in the thalamus SUFFICIENT to intefere with a cognitive function? Aranda Duan Carmen Verela Matt Wilson

0-Back 1-Back 2-Back Arch Gen Psychiatry. 2003 Sep;60(9):889-96.
Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotypeand schizophrenia. Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS, Goldman D, Weinberger DR. 0-Back 1-Back 2-Back

Representation of behavioral context in the nucleus reuniens for CA1 place cells. H. T. ITO, M. P. WITTER, E. I. MOSER, M.-B. MOSER; TRONHEIM, Norway A potential source of information about behavioral context is the medial prefrontal cortex (mPFC) (Jones and Wilson, 2005; Fujisawa et al., 2008), but neurons in mPFC do not directly project to CA1. The mPFC instead has reciprocal anatomical connections with the midline thalamic nucleus reuniens (Re), and neurons in Re give rise to a major excitatory input to CA1 (Herkenham, 1978; Wouterlood et al. 1990; Dolleman-Van der Weel et al., 1993; Vertes et al., 2007). The Re may therefore have an important relay function in transferring information about behavioral context from mPFC to the CA1. To test this idea, we recorded the activity of neurons in Re and CA1 simultaneously, when animals were performing a continuous alternation task in a figure-8 maze. In this task, many CA1 neurons with place fields at the stem of the maze showed a trajectory-dependent change in their peak firing rate, as previously reported (Wood et al., 2000). Under the same condition, a significant proportion of Re neurons also showed trajectory-dependent activity, changing their firing rate depending on the animal’s path. To test the influence of Re activity on CA1, we made lesions of Re, which significantly reduced the rate change of CA1 place cells observed at the stem of the maze. We also found that a trajectory-dependent rate change of CA3 place cells, which do not receive input from the Re, was significantly smaller than that of CA1 place cells. These results together suggest that Re is likely a source of trajectory-dependent information to CA1. Taken together, our results point to the Re as a possible source of contextual input to CA1 place cells.

Goal: to test whether delta in the thalamus can be CAUSAL in producing symptoms of SZ.
Strategy: induce delta in RE using channel-rhodopsin. Spike pattern in Reuniens during ketamine LFP trace in Reuniens during ketamine Light pattern used to stimulate Channel-rhodopsin in Reuniens

Testing in 4 consecutive days
(black: without light; blue: with light) N=5 Training process (n =5) Probability correct Probability correct Collaboration with Carmen Varela and Matt Wilson, MIT Yuchun Zhang and Aranda Duan, Brandeis

T-type Ca channel implicated by GWAS study
Nature. 2014 Biological insights from 108 schizophrenia-associated genetic loci. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Multivariate genetic determinants of EEG oscillations in schizophrenia and psychotic bipolar disorder from the BSNIP study. Narayanan B, Soh P, Calhoun VD, Ruaño G, Kocherla M, Windemuth A, Clementz BA, Tamminga CA, Sweeney JA, Keshavan MS, Pearlson GD. Transl Psychiatry. 2015

What is the basis of the sudden onset of psychosis (the psychotic break)
Can we understand how abnormal delta oscillations would give rise to cognitive, positive and negative symptoms of Schizophrenia?

Corollary discharge CA1 reuniens mPFC Fast spiking interneuron Delta Previous trial nRT Gamma NR2C D2 T-type Ca channel Psychosis from delta generated by positive feedback in the hippocampus- VTA-thalamus loop. Delta jams communication through particular thalamic nuclei. VTA

Partial Predisposition
Schizophrenia as a bistable system: Predisposition (such as NMDA hypofunction) or Stress by themselves are not sufficient to induce positive feedback, but together induce positive feedback (producing delta oscillations). This persists even after stress is removed. See article in Biological Psychiatry. Buonanno, 2007; expression of NR2C develops in adolescence. Predisposition Partial

Schneider's first-rank symptoms of schizophrenia are symptoms which, if present, are strongly suggestive of schizophrenia. The first-rank symptoms of schizophrenia include: auditory hallucinations: hearing thoughts spoken aloud hearing voices referring to himself / herself, made in the third person auditory hallucinations in the form of a commentary thought withdrawal, insertion and interruption thought broadcasting somatic hallucinations delusional perception feelings or actions experienced as made or influenced by external agents

Other targets of reuniens
Concept of corollary discharge Hippocampus Thalamus Corollary discharge CA1 reuniens mPFC Fast spiking interneuron Delta Previous trial nRT Gamma NR2C D2 T-type Ca channel Psychosis from delta generated by positive feedback in the hippocampus- VTA-thalamus loop. Delta jams communication through particular thalamic nuclei. Other midline thalamic nuclei VTA

End of talk

Parafasicular and centromedial midline thalamic nuclei
How low frequency synchronized bursting in the midline thalamus causes NEGATIVE symptoms of schizophrenia (avolition) 1). NMDAR antagonist action in thalamus imposes δ oscillations on the hippocampus. Zhang Y, Yoshida T, Katz DB, Lisman JE. J Neurophysiol Jun;107(11):3181-9 2) Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Threlfell S, Lalic T, Platt NJ, Jennings KA, Deisseroth K, Cragg SJ. Neuron Jul 12;75(1):58-64. 3) Thalamic gating of corticostriatal signaling by cholinergic interneurons. Ding JB, Guzman JN, Peterson JD, Goldberg JA, Surmeier DJ. Neuron Jul 29;67(2): A proposed hypothalamic-thalamic-striatal axis for the integration of energy balance, arousal, and food reward. Kelley AE, Baldo BA, Pratt WE. J Comp Neurol Dec 5;493(1):72-85. 4) Dissociation of hedonic reaction to reward and incentive motivation in an animal model of the negative symptoms of schizophrenia. Ward RD, Simpson EH, Richards VL, Deo G, Taylor K, Glendinning JI, Kandel ER, Balsam PD. Neuropsychopharmacology Jun;37(7): Negative symptoms of schizophrenia are associated with abnormal effort-cost computations. Gold JM, Strauss GP, Waltz JA, Robinson BM, Brown JK, Frank MJ. Biol Psychiatry Jul 15;74(2): doi: /j.biopsych Epub 2013 Feb 7. Parafasicular and centromedial midline thalamic nuclei 1) Abnormal delta frequency synchronized oscillations in SZ. cortex STRIATUM 2) Synchronized input enhances Ach release D2 d1 Cholinergic TAN 3) M4 muscarinic enhancement of postsynaptic integration in D2 medium spiny cells No-go pathway (indirect) go pathway (direct) SNpc 5) Ach (nicotinic) releases DA from terminals, causing pause in firing of TAN 4) Avolition results from enhancement of No-go pathway relative to Go pathway. Thalamic paraventricular nucleus neurons collateralize to innervate the prefrontal cortex and nucleus accumbens. Bubser M, Deutch AY. Brain Res Mar 23;787(2):

Elevated Delta is seen in the 22qll model of SZ (see below) and in the neonatal ventral hippocampal model of SZ Nature Apr 1;464(7289):763-7. Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Sigurdsson T, Stark KL, Karayiorgou M, Gogos JA, Gordon JA.

Hippocampus Thalamus reuniens mPFC Delta nRT NR2C D2 VTA Gamma
Positive symptoms: deficit in corollary discharge to temporal lobe prevents sense of self Cognitive symptoms: deficit in signal from mPFC prevents delayed alternation working memory task Hippocampus Thalamus Corollary discharge CA1 reuniens mPFC Fast spiking interneuron Delta Previous trial CM parafasicular nRT Gamma NR2C D2 Psychosis from positive feedback in the hippocampus- VTA-thalamus loop Negative symptoms: delta bursting in CM/parafasicular excites TANs in striatum, which excites indirect (No-go) pathway, producing avolition. VTA

Pharmacological strategies for blocking abnormal delta
T-channel antagonists (e.g. Merck drug or ethosuximide) Inactivating T-channels by depolarizing thalamic neurons. Intefering with transfer of oscillations from nRT to relay nuclei

Thalamus Relay reuniens CA1 hippocampal region Medial PFC
Hyperactivation in SZ Medial PFC antipsychotics cFOS NMDAR Nucleus reticularis Dopamine promotes delta oscillations NMDAR Delta frequency oscillations originating in particular thalamic nuclei create a functional disconnection syndrome, preventing normal communication between cortical/hippocampal region. VTA

Conclusion: Delta oscillations in subregions of the thalamus “jam” communication through the thalamus, thereby producing a functional disconnection. Evidence for disconnection in SZ: Tononi; Ford and Mathalon Can this explain positive and negative symptoms?

thalamus Relay cell nRT
Therapeutic action by antagonist of modulators that hyperpolarize Alpha2 adrenergic, D2 dopamine A1 adenosine Y1 receptors for NPY (NeuroPeptide Y) Therapeutic action by agonist of modulators that depolarize Alpha1 and beta-adrenergic H1 and H2 histamine m1 and m3 muscarinic nicotinic VPAC2 receptors for VIP (Vasoactive Intestinal Peptide) PAC1 receptors for PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide) orexin TRH D1 dopamine NR2C thalamus Relay cell nRT Therapeutic action via block of ion channels necessary for bursting: K+, Na+, Ih, T-channels, TASK, GIRK Therapeutic action by blocking transmission Gaba B antagonist mGluR2/3 agonist m2 muscarinic agonist

End of talk

BOLD: ketamine produces decrease in metabolism in vmPFC (blue)
In Schizophrenia spectrum disorder there is a source of theta/delta in vmPFC BOLD: ketamine produces decrease in metabolism in vmPFC (blue) Increase in metabolism in thalamus and hippocampus.(not shown) Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Deakin JF, Lees J, McKie S, Hallak JE, Williams SR, Dursun SM. Arch Gen Psychiatry Feb;65(2):154-64 Front Hum Neurosci. 2011;5:69. Epub 2011 Jul 29. Imaging of thalamocortical dysrhythmia in neuropsychiatry. Schulman JJ, Cancro R, Lowe S, Lu F, Walton KD, Llinás RR.

Elliot Hong L, Moran LV, Du X, O'Donnell P, Summerfelt A.
Mismatch negativity and low frequency oscillations in schizophrenia families. Elliot Hong L, Moran LV, Du X, O'Donnell P, Summerfelt A. Clin Neurophysiol. 2012 Enhanced delta is NOT seen in their first degree relatives {Clementz, 1994 ; Sponheim, 2003 ;Venables, 2009}. Even in twins discordant for schizophrenia increased delta was not observed in the healthy twin {Stassen, 1999 ;Weisbrod, 2004}.

No-go basal ganglia circuitry Negative symptoms
The onset of psychosis during the schizophrenic break occurs when the hippocampus, VTA and midline thalamus go into a positive feedback loop that generates delta, thereby blocking corollary discharge from the mPFC to the temporal lobe. There is an interneuron abnormality (gamma abnormality) that precedes the schizophrenic break, but enhances the probability of positive feedback. Hippocampus Thalamus Corollary discharge Corollary discharge reuniens mPFC Fast spiking interneuron Delta Other midline nuclei Gamma nRT No-go basal ganglia circuitry Negative symptoms VTA

Ketamine injection into the reuniens increases hippocampal delta and increases the firing rate of CA1 cells

Systemic NMDAR antagonist (Ketamine; 50mg/kg) enhances delta power in the CA1 hippocampal region. The firing rate and gamma power are also increased.

Muscimol injection into the reuniens blocks the enhancement of delta power by systemic ketamine
Ketamine-induced gamma is NOT blocked by muscimol

Thalamus Relay reuniens CA1 hippocampal region Medial PFC
Hyperactivation in SZ Medial PFC antipsychotics cFOS NMDAR Nucleus reticularis Dopamine promotes delta oscillations NMDAR Delta frequency oscillations originating in particular thalamic nuclei create a functional disconnection syndrome, preventing normal communication between cortical/hippocampal region. VTA

NMDA hypofunction theory (NMDAR antagonists given to humans induce all major symptoms of the disease) Dopamine hyperfunction theory (D2 antagonists produce effective treatment of schizophrenia) Interneuron theory (postmortem tissue shows a reduction of GAD and parvalbumin in fast-spiking interneurons)

Is the delta abnormality seen in animal models of SZ?

Physiol Behav. 2007 Oct 22;92(3):461-7. Epub 2007 Apr 22.
Sleep and EEG profile in neonatal hippocampal lesion model of schizophrenia. Ahnaou A, Nayak S, Heylen A, Ashton D, Drinkenburg WH.

Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. Lodge DJ, Grace AA. J Neurosci Oct 17;27(42): ttx In MAM model, elevated dopamine actiivty is reduced by ttx injection into hippocampus

Psychosis from positive feedback in the hippocampus/VTA/thalamus loop
The onset of psychosis during the schizophrenic break occurs when the hippocampus, VTA and midline thalamus go into a positive feedback loop that generates delta, thereby blocking corollary discharge from the mPFC to the temporal lobe. There is an interneuron abnormality (gamma abnormality) that precedes the schizophrenic break, but enhances the probability of positive feedback. Hippocampus Thalamus Corollary discharge Corollary discharge reuniens mPFC Fast spiking interneuron Delta Other relay nuclei Gamma nRT Psychosis from positive feedback in the hippocampus/VTA/thalamus loop VTA

Predisposition due to interneuron abnormality.
Summary: There is evidence for excitatory effects at all three connections in the thalamus-hippocampus-VTA-thalamus loop Hippocampus Thalamus Corollary discharge Corollary discharge reuniens mPFC Fast spiking interneuron Delta Other relay nuclei Gamma nRT What causes the loop to go into positive feedback at the schizophrenia break? Predisposition due to interneuron abnormality. Stress-induced release of dopamine VTA

Schneider's first-rank symptoms of schizophrenia are symptoms which, if present, are strongly suggestive of schizophrenia. The first-rank symptoms of schizophrenia include: auditory hallucinations: hearing thoughts spoken aloud hearing voices referring to himself / herself, made in the third person auditory hallucinations in the form of a commentary thought withdrawal, insertion and interruption thought broadcasting somatic hallucinations delusional perception feelings or actions experienced as made or influenced by external agents

Aversive stimuli alter ventral tegmental area dopamine neuron activity via a common action in the ventral hippocampus. Valenti O, Lodge DJ, Grace AA. J Neurosci Mar 16;31(11): The effect of acute restraint (AR) is blocked by TTX injection into the ventral hippocampus.

The delta oscillations that are abnormal in SZ can be mimicked by NMDAR antagonist action in the thalamus. The mechanisms involve T-type Ca channels and NR2C. Delta oscillations in the midline reuniens nuclei interfere with working memory and perhaps other forms of PFC-temporal lobe communication, generating psychosis. Delta correlates with psychosis; the interneuron/gamma abnormality is a predisposition. The combination of predisposition and stress throw the thalamus-hippo-VTA loop into a positive feedback state that generates delta and psychosis. Hippocampus Thalamus Corollary discharge Corollary discharge reuniens mPFC Fast spiking interneuron Delta Other relay nuclei Gamma nRT VTA

The input to the hippocampus is from the midline thalamic nucleus, the nucleus reuniens.
According to the thalamocortical dysrhythmia hypothesis, the nature of the disease is determined by which thalamic nuclei generate delta/theta oscillations.

The midline thalamic nucleus, the nucleus reuniens, is the ONLY thalamic innervation of the hippocampus. The reuniens does not innervate the dentate or CA3, but does innervate CA1. It is therefore of interest that in SZ, CA1 is selectively hyperactive (next slide).

Firing rate model: In steady state,

We wanted to test the hypothesis that the delta state in the reuniens could drive delta in CA1. We also wanted to know if the overall level of CA1 activity is increased. Such hyperactivity could drive the dopamine system, which, in turn, promotes delta in thalamus. We have previously proposed (Biol Psychiatry) that the thalamus-hippocampus-VTA loop could go into positive feedback.

Systemic NMDAR antagonist (Ketamine) evokes delta oscillations in the nucleus reuniens

NMDA hypofunction theory (NMDAR antagonists given to humans induce all major symptoms of the disease) Dopamine hyperfunction theory (D2 antagonists produce effective treatment of schizophrenia) Interneuron theory (postmortem tissue shows a reduction of GAD and parvalbumin in fast-spiking interneurons) NEW THEORY THAT ENCOMPASSES THE OLD: Delta oscillations theory. The interneurons abnormality greats hyperactivity that produces mild cognitive symptoms and produces a PREDISPOSITION for schizophrenia. Psychosis occurs rather suddenly when a loop involving the thalamus, hippocampus and VTA goes into a positive feedback state characterized by delta oscillations. Only a small part of the thalamus is involved (probably the nucleus reuniens) and this blocks the flow of corollary discharge from the mPFC to the temporal lobe. The loss of corollary discharge produces the deficits in sense of self that constitute a core symptom of the disease.

Neonatal damage to hippocampus produces hyperactivity, increased gamma and hyperdopaminergic state, making a PREDISPOSITION to psychosis Hippocampus Thalamus Corollary discharge reuniens Fast spiking interneuron Delta Other relay nuclei Gamma nRT Psychosis from positive feedback Hippocampal VTA loop VTA Model of psychotic break based: predisposition allows stress to trigger positive feedback in VTA-thalamic-hippocampal loop

Partial Predisposition
Schizophrenia as a bistable system: Predisposition (such as NMDA hypofunction) or Stress by themselves are not sufficient to induce positive feedback, but together induce positive feedback (producing delta oscillations). This persists even after stress is removed. See article in Biological Psychiatry. Buonanno, 2007; expression of NR2C develops in adolescence. Predisposition Partial

Hippocampus Thalamus PFC reuniens mPFC Delta nRT Theta VTA
Neonatal damage to hippocampus produces hyperactivity and hyperdopaminergic state Hippocampus Thalamus PFC Corollary discharge Corollary discharge reuniens mPFC Fast spiking interneuron Delta Other relay nuclei Gamma nRT Psychosis from positive feedback Hippocampal VTA loop Abnormal PFC development as a results of hyperdopaminergic state Theta VTA Medial septal nucleus How might delta oscillations in the thalamo-hippocampal-VTA loop produce symptoms? One hypothesis is that it blocks corollary discharge from the PFC from getting to the temporal lobe (via the reuniens pathway).

A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. Lodge DJ, Behrens MM, Grace AA. J Neurosci Feb 25;29(8):

During delta, there are substantial periods during each cycle when no firing occurs. For this reason, regions in which delta occurs may be minimally functional, yield “disconnection”. Brain Sep;133(9): Epub 2010 Jul 23. Laminar analysis of slow wave activity in humans. Csercsa R, Dombovári B, Fabó D, Wittner L, Eross L, Entz L, Sólyom A, Rásonyi G, Szucs A, Kelemen A, Jakus R, Juhos V, Grand L, Magony A, Halász P, Freund TF, Maglóczky Z, Cash SS, Papp L, Karmos G, Halgren E, Ulbert I.

Hypothesis (Predisposition and Psychotic Break):
Schizophrenia is a dysrhythmia originating in the thalamus that results in sleep-like delta frequency oscillations in the awake state (Llinas). These oscillations occur only in subregions of the thalamocortical system (vmPFC/midline thalamus, hippocampus). The abnormal oscillations can be/ mimicked by block of NR2C type of NMDAR in the gabaergic neurons of the nucleus reticularis of the thalamus. The delta oscillations induced by NMDAR antagonist require D2 action. Delta oscillations in the nucleus reuniens of the thalamus transmits delta to the hippocampus and vmPFC, where they interfere with 1) hipppocampal memory processes and 2) the information flow from the mPFC to the temporal lobe required for a sense of self. There is an interneuron endophenotype that results in gamma frequency abnormalities and disinhibition. This makes a predisposition for the psychotic break. The break occurs when the thalamic-hippocampal-VTA loop goes into positive feedback and the delta oscillations are increased.

Genetic influences and prenatal insults produce interneuron abnormality and gamma abnormality, thereby creating predisposition for SZ by bringing the thalam-hippocampal-VTA loop closer to the threshold for positive feedback. Stress raises dopamine further. This hyperpolarizes the nRT cells and pushes the loop over the threshold for positive feedback, creating delta oscillations in midline thalamus, hippocampus and mPFC. This is the “psychotic break”. Delta oscillations in the midline thalamus interfere with the corollary discharge normally passed from mvPFC to the temporal lobe, thereby contributing to the first rank symptoms of the disease.

END Delta is synptom: NMDA hypothesis action in thalamus
Nmda makes delta This is an action in the thalamus Special role of reuniens is delta causal*** *** why psychosis aout self—disconnection Psychotic break*** positive feedback**gamma delta abnormaltiy***

Delta frequency firing of nucleus reticularis cells during slow-wave sleep
Mukhametov et al, 1970

Major theories of schizophrenia

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