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An explanation of why schizophrenia begins with excitotoxic damage to the hippocampus
Medical Hypotheses 81 (2013) 1056–1058
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
An explanation of why schizophrenia begins with excitotoxic damage to the hippocampus Arnold E. Eggers ⇑ SUNY-Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, United States Kings County Hospital, 451 Clarkson Ave., Brooklyn, NY 11203, United States
a r t i c l e
i n f o
Article history: Received 8 August 2013 Accepted 26 September 2013
a b s t r a c t A recent paper by Schobel et al. provides evidence that schizophrenia begins with excitotoxic damage in the hippocampus, primarily in the CA1 subfield. MRI measurement of cerebral blood volume (CBV) was taken to be a marker of basal metabolism. High baseline CBV in the CA1 subfield of subjects at high risk for schizophrenia predicted progression to psychosis and the development of hippocampal atrophy. A mouse model of ketamine excitotoxicity reproduced the human imaging study, i.e. hypermetabolism in CA1 led to atrophy. The authors do not explain the pathophysiology of selective excitotoxicity in the hippocampus. A recently published serotonin theory of schizophrenia provides a hypothetical explanation for these findings. The serotonin theory predicts that schizophrenia begins with stress-induced overdrive of serotonergic pacemaker cells in the dorsal raphe nucleus. The overdrive is passed via the entorhinal cortex to the hippocampus, where it causes excitotoxicity. Passage through the entorhinal cortex converts a serotonergic signal into a glutamate signal, glutamate being the neurotransmitter of exicitotoxicity. The remitting-relapsing pattern of schizophrenia is explained by a balance between excitotoxicity in the hippocampus and repopulation by neurogenesis in the subgranular zone. Injury is balanced by healing. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction A recent paper by Schobel et al. provides evidence that schizophrenia begins with excitotoxic damage to the hippocampus [1]. They used contrast-enhanced T1-weighted MRI to do serial measurements of cerebral blood volume (CBV), which is a marker of basal metabolism, in the CA1 subfield of the anterior hippocampus in 25 subjects at clinical high-risk for progressing to a psychotic disorder. Increased baseline CBV in the CA1 region, particularly on the left side, was known from a previous study to be predictive of clinical progression to psychosis [2]. In this study they confirmed that finding and added to it the observation that clinical worsening and increasing CBV both correlated with the development of atrophy in the CA1 region. Hypermetabolism preceded atrophy. They then presented data from an animal model to support the idea that the hypermetabolism represented excitotoxicity. Three times weekly subcutaneous injections of ketamine in young mice led to selective increase in CBV in the CA1 subfield which was followed by atrophy, or slowed growth, in the same area. Their ⇑ Address: SUNY-Downstate Medical Center, Box 1213, Department of Neurology, Brooklyn, NY 11203, United States. Tel.: +1 718 270 2051; fax: +1 718 270 3840. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.09.033
interpretation of the data was that ketamine blocked the NMDA receptor, increasing the extracellular concentration of free glutamate in the synaptic cleft because of decreased binding of glutamate to NMDA receptors; free glutamate then bound at toxic levels to AMPA receptors, causing excitotoxic cell death. The CA1 region has particularly high concentrations of both NMDA and AMPA receptors, which explains its vulnerability [3]. Pretreatment of mice with LY379268, a drug that activates presynaptic metabotropic glutamate receptors which are inhibitory to glutamate release, protected the mice against both the ketamineinduced rise in CBV and ketamine-induced hippocampal atrophy. The authors argue persuasively by analogy that the CA1 hypermetabolism which precedes CA1 atrophy in human patients is likely to represent excitotoxicity. They suggest that hypermetabolism caused by high extracellular glutamate is a brain-wide feature of schizophrenia which ‘‘during prodromal stages. . .is restricted to relatively confined areas of the brain’’ [1]. The problem with this interpretation is that, in the first paper from the same group, increased CBV was not observed brain-wide in either prodromal or psychotic patients [2]. In particular, increased CBV was not seen in the dorsolateral prefrontal cortex (DLPFC), which is one the areas of the brain which undergoes the greatest loss of grey matter in schizophrenia; in fact, CBV in the DLPFC was slightly decreased in high-risk subjects compared to normal controls and
A.E. Eggers / Medical Hypotheses 81 (2013) 1056–1058
statistically-significantly low in schizophrenics [2,4]. Therefore, it seems unlikely that loss of grey matter is, in general, preceded by hypermetabolism. The temporal sequence of excitotoxicity leading to atrophy is specific to the hippocampus at the onset of the disease. A relevant question to ask is whether axon terminals in CA1 release excess glutamate in response to a normal number of action potentials coming down the axon; whether serotonin reuptake is decreased; or whether there are simply more action potentials. The correct answer to the question, according to this theory, is the last.
Negative feedback loop between dorsal raphe nucleus (DRN) and hippocampus A serotonin theory of schizophrenia has been published which starts by postulating a negative feedback loop which runs between the DRN and the hippocampus and which functions normally to control the rate of neurogenesis in the hippocampus [5,6]. A direct serotonergic projection from DRN to hippocampus promotes neurogenesis, which, should it become excessive, leads to greater feedback inhibition of the DRN and a return to equilibrium. If neurogenesis falters and feedback inhibition weakens, then more serotonin will be released in the hippocampus, which would again restore equilibrium. The anatomical substrate of this loop was described by Nauta [7]. The DRN is a pacemaker nucleus theoretically capable of driving the firing rates of other neurons [5,6]. It is hypothesized that severe acute stress can cause the DRN to go into overdrive, which is transmitted indirectly via the entorhinal cortex (another pacemaker nucleus) to the hippocampus, where it causes excitotoxic cell death. Passage through the entorhinal cortex converts a serotonergic signal into a glutamate signal, glutamate being the neurotransmitter associated with excitotoxicity. The normal feedback loop back to the DRN is then broken and cannot restore itself if a radically disinhibited DRN has gone into sustained overdrive and constantly kills dentate neurons. This is a mechanism by which severe acute stress, particularly if sustained or recurrent, can perpetuate itself and lead to chronic new patterns of neuronal firing over large areas of the brain. The DRN projects diffusely to the entire brain and, because of its pacemaker properties, it can have a large impact on brain function. In the case of schizophrenia, serotonergic overdrive targets the cerebral cortex, especially the anterior cingulate cortex and dorsolateral frontal lobe. This leads to two things [1]: overactivity of cytosolic phospholipse A2 linked to 5HT2A/2C receptors causes both cerebral and systemic deficiency of x-3 and x-6 phospholipids; and [2] excessive serotonin input into the cortex leads to a disruption of normal action potential generation by targeted neurons, which become hypometabolic. Because of loss of mutual reciprocal innervation between large areas of the cerebral cortex, denervation atrophy ensues; shrinkage of neuronal cell bodies and loss of neuropil account for the loss of grey matter which is the basis of brain atrophy in schizophrenia [4]. Normal dopamine input into an impaired anterior cingulated cortex causes positive symptoms and frontal lobe hibernation causes negative symptoms and cognitive impairment. The newer neuroleptics, in contrast to the older ones, can slow down the course of the disease because they block 5HT2A/2C receptors as well as dopamine receptors. They treat pathophysiology, not just symptoms. There is not room in this paper to repeat in detail the extensive literature review supporting this theory. The functional importance of the DRN-hippocampus loop cannot be demonstrated directly but must be inferred because schizophrenia is a disease which is unique to human beings and cannot be fully modeled in animals. DRN overdrive has been imaged by PET scan during mi-
1057
graine headaches; migraine, along with hypertension and metabolic syndrome (especially that seen in untreated schizophrenia), is posited to have a special relationship to schizophrenia [4,8]. This cluster of diseases, all of which are uniquely human, are hypothesized to share a similar pathophysiology involving the DRN-hippocampus loop [5]. DRN overdrive like that imaged during migraine attacks is hypothesized to occur with or without headache in all these diseases in response to stress. Excitotoxic cell death in the hippocampus is the second step of the pathophysiolgy, and aberrant disinhibited serotonergic function is the third step, the one that causes the various diseases. The pattern of dysfunctional serotonergic overdrive is different for each disease; genetic factors may relate to the ‘‘choice of disease’’. Hypothesis The excitoxicity in the hippocampus imaged in the Schobel paper is caused by stress-induced serotonergic overdrive passing from the DRN to the hippocampus via the entorhinal cortex. Discussion An excessive neuronal drive making its way through the hippocampal circuitry, from entorhinal cortex to dentate to CA3 to CA1 to subiculum, may not affect each subfield of the hippocampus equally. Mesial temporal sclerosis, which is thought to be caused by excessive epileptic discharges occurring, for example, in febrile convulsions in infants and young children, affects CA1 more than any other region of the hippocampus, as is the case with the Schobel mouse model and with schizophrenia [1,2,9]. The concordance between the three pathologies strengthens the excitotoxic interpretation of the two diseases. As mentioned above, CA1 pyramidal neurons express particularly high levels of both NMDA and AMPA receptors which may explain why it is particularly damaged as the excitotoxic train makes its way through hippocampal circuitry [3]. A purely genetic disease without environmental interplay will not have remissions and relapses. The relationship of stress to worsening in schizophrenia is the best documented environmental interplay in the disease. Brown and Birley interviewed 37 patients with onset of first episode schizophrenia and 13 patients with progression from mild to severe schizophrenia [10] They defined an ‘‘event’’ as one of any of a detailed list of possible major changes or crises in a person’s life, and found that, compared to controls from the general population, schizophrenics had an increased incidence of events (60% vs. 19%). Nuechterlein et al., proposed a ‘‘vulnerability/stress model of schizophrenic relapse’’ [11]. They studied relapse in patients compliant with medication compared to patients off medication. Medicated patients had a tenfold higher incidence of ‘‘independent life events’’ in the month prior to a relapse compared to months that did not precede a relapse. This pattern did not hold for patients off medication, which the authors interpreted as showing that medication raised the threshold for how stressful an event had to be in order to induce relapse. Increased stress, particularly crime-related and poverty-related stress, is a possible explanation for why people in lower socioeconomic brackets and migrant populations have a higher incidence of schizophrenia. It is true that many patients do seem to progress gradually into psychosis without a dramatic stressor; however, they may be hypersensitive to the small stressors of average everyday life. Remission Besides excitotoxicity, another part of the serotonin theory of schizophrenia is that healing of the hippocampus, primarily the
1058
A.E. Eggers / Medical Hypotheses 81 (2013) 1056–1058
dentate, can occur because of neurogenesis in the subgranular zone [4,5]. This is difficult but can occur, at least to an extent. Repopulation of the hippocampus restores the negative feedback loop and leads to symptomatic improvement. The hippocampus, including the granule cell layer of the dentate, has a rich distribution of S1 receptors, in contrast to S2 receptors, which are expressed relatively poorly in Ammon’s horn compared to neocortex and absent in the granule cell layer [12,13]. S2 receptors are associated with serotonin overdrive in the entorhinal cortex and frontal lobe and S1 receptors with healing in the dentate. Anti-depressants are thought to act via stimulating neurogenesis. Long-term lithium administration increases serotonin release in the hippocampus [14]. Anti-depressants and lithium might possibly be useful adjunct treatments in schizophrenia. Conflict of interest None. References [1] Schobel SA, Chaudhury NH, Khan UA, Paniagua B, Styner MA, et al. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron 2013;78:81–93. [2] Schobel SA, Lewandowski NM, Corcoran CM, Moore H, Brown T, et al. Differential targeting of the CA1 subfield of the hippocampal formation by
[3]
[4] [5]
[6] [7] [8] [9]
[10] [11]
[12]
[13] [14]
schizophrenia and related psychotic disorders. Arch Gen Psychiatry 2009;66:938–46. Coultrap SJ, Nixon KM, Alvestad RM, Valenzuela CF, Browning MB. Differential expression of NMDA receptor subunits and splice variants among the CA1, CA3, and dentate gyrus of the adult rat. Mol Brain Res 2005;135:104–11. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999;122:593–624. Eggers AE. Extending David Horrobin’s membrane phospholipid theory of schizophrenia: overactivity of cytosolic phospholipase A2 in the brain is caused by overdrive of coupled serotonergic 5HT2A/2C receptors in response to stress. Med Hypotheses 2012;79:740–3. Eggers AE. A serotonin hypothesis of schizophrenia. Med Hypotheses 2013;80:791–4. Nauta WJH. Hippocampal projections and related neural pathways to the midbrain in the cat. Brain 1958;81:319–40. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995;1:658–60. Mathern GW, Babb TL, Armstrong DL. Hippocampal sclerosis. In: Engel J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia, USA: Lippincott-Raven Publishers; 1997. p. 133–55. Brown GW, Birley JLT. Crises and life changes and the onset of schizophrenia. J Health Soc Behav 1968;9:203–14. Nuechterlein KH, Dawson ME, Ventura J, Gitlin M, Subotnik KL, et al. The vulnerability/stress model of schizophrenic relapse: a longitudinal study. Acta Psychiatr Scand 1994;89(Suppl. 382):58–64. Pompeiano M, Palacios JM, Mengod G. Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci 1992;12:440–53. Pompeiano M, Palacios JM, Mengod G. Distribution of the 5-HT2A and 5-HT2C receptors. Mol Brain Res 1994;23:163–78. Treiser SL, Cascio CS, O’Donohue TL, Thoa NB, Jacobowitz DM, et al. Lithium increases serotonin release and decreases serotonin receptors in the hippocampus. Science 1981;213:1529–31.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
An explanation of why schizophrenia begins with excitotoxic damage to the hippocampus Arnold E. Eggers ⇑ SUNY-Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, United States Kings County Hospital, 451 Clarkson Ave., Brooklyn, NY 11203, United States
a r t i c l e
i n f o
Article history: Received 8 August 2013 Accepted 26 September 2013
a b s t r a c t A recent paper by Schobel et al. provides evidence that schizophrenia begins with excitotoxic damage in the hippocampus, primarily in the CA1 subfield. MRI measurement of cerebral blood volume (CBV) was taken to be a marker of basal metabolism. High baseline CBV in the CA1 subfield of subjects at high risk for schizophrenia predicted progression to psychosis and the development of hippocampal atrophy. A mouse model of ketamine excitotoxicity reproduced the human imaging study, i.e. hypermetabolism in CA1 led to atrophy. The authors do not explain the pathophysiology of selective excitotoxicity in the hippocampus. A recently published serotonin theory of schizophrenia provides a hypothetical explanation for these findings. The serotonin theory predicts that schizophrenia begins with stress-induced overdrive of serotonergic pacemaker cells in the dorsal raphe nucleus. The overdrive is passed via the entorhinal cortex to the hippocampus, where it causes excitotoxicity. Passage through the entorhinal cortex converts a serotonergic signal into a glutamate signal, glutamate being the neurotransmitter of exicitotoxicity. The remitting-relapsing pattern of schizophrenia is explained by a balance between excitotoxicity in the hippocampus and repopulation by neurogenesis in the subgranular zone. Injury is balanced by healing. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction A recent paper by Schobel et al. provides evidence that schizophrenia begins with excitotoxic damage to the hippocampus [1]. They used contrast-enhanced T1-weighted MRI to do serial measurements of cerebral blood volume (CBV), which is a marker of basal metabolism, in the CA1 subfield of the anterior hippocampus in 25 subjects at clinical high-risk for progressing to a psychotic disorder. Increased baseline CBV in the CA1 region, particularly on the left side, was known from a previous study to be predictive of clinical progression to psychosis [2]. In this study they confirmed that finding and added to it the observation that clinical worsening and increasing CBV both correlated with the development of atrophy in the CA1 region. Hypermetabolism preceded atrophy. They then presented data from an animal model to support the idea that the hypermetabolism represented excitotoxicity. Three times weekly subcutaneous injections of ketamine in young mice led to selective increase in CBV in the CA1 subfield which was followed by atrophy, or slowed growth, in the same area. Their ⇑ Address: SUNY-Downstate Medical Center, Box 1213, Department of Neurology, Brooklyn, NY 11203, United States. Tel.: +1 718 270 2051; fax: +1 718 270 3840. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.09.033
interpretation of the data was that ketamine blocked the NMDA receptor, increasing the extracellular concentration of free glutamate in the synaptic cleft because of decreased binding of glutamate to NMDA receptors; free glutamate then bound at toxic levels to AMPA receptors, causing excitotoxic cell death. The CA1 region has particularly high concentrations of both NMDA and AMPA receptors, which explains its vulnerability [3]. Pretreatment of mice with LY379268, a drug that activates presynaptic metabotropic glutamate receptors which are inhibitory to glutamate release, protected the mice against both the ketamineinduced rise in CBV and ketamine-induced hippocampal atrophy. The authors argue persuasively by analogy that the CA1 hypermetabolism which precedes CA1 atrophy in human patients is likely to represent excitotoxicity. They suggest that hypermetabolism caused by high extracellular glutamate is a brain-wide feature of schizophrenia which ‘‘during prodromal stages. . .is restricted to relatively confined areas of the brain’’ [1]. The problem with this interpretation is that, in the first paper from the same group, increased CBV was not observed brain-wide in either prodromal or psychotic patients [2]. In particular, increased CBV was not seen in the dorsolateral prefrontal cortex (DLPFC), which is one the areas of the brain which undergoes the greatest loss of grey matter in schizophrenia; in fact, CBV in the DLPFC was slightly decreased in high-risk subjects compared to normal controls and
A.E. Eggers / Medical Hypotheses 81 (2013) 1056–1058
statistically-significantly low in schizophrenics [2,4]. Therefore, it seems unlikely that loss of grey matter is, in general, preceded by hypermetabolism. The temporal sequence of excitotoxicity leading to atrophy is specific to the hippocampus at the onset of the disease. A relevant question to ask is whether axon terminals in CA1 release excess glutamate in response to a normal number of action potentials coming down the axon; whether serotonin reuptake is decreased; or whether there are simply more action potentials. The correct answer to the question, according to this theory, is the last.
Negative feedback loop between dorsal raphe nucleus (DRN) and hippocampus A serotonin theory of schizophrenia has been published which starts by postulating a negative feedback loop which runs between the DRN and the hippocampus and which functions normally to control the rate of neurogenesis in the hippocampus [5,6]. A direct serotonergic projection from DRN to hippocampus promotes neurogenesis, which, should it become excessive, leads to greater feedback inhibition of the DRN and a return to equilibrium. If neurogenesis falters and feedback inhibition weakens, then more serotonin will be released in the hippocampus, which would again restore equilibrium. The anatomical substrate of this loop was described by Nauta [7]. The DRN is a pacemaker nucleus theoretically capable of driving the firing rates of other neurons [5,6]. It is hypothesized that severe acute stress can cause the DRN to go into overdrive, which is transmitted indirectly via the entorhinal cortex (another pacemaker nucleus) to the hippocampus, where it causes excitotoxic cell death. Passage through the entorhinal cortex converts a serotonergic signal into a glutamate signal, glutamate being the neurotransmitter associated with excitotoxicity. The normal feedback loop back to the DRN is then broken and cannot restore itself if a radically disinhibited DRN has gone into sustained overdrive and constantly kills dentate neurons. This is a mechanism by which severe acute stress, particularly if sustained or recurrent, can perpetuate itself and lead to chronic new patterns of neuronal firing over large areas of the brain. The DRN projects diffusely to the entire brain and, because of its pacemaker properties, it can have a large impact on brain function. In the case of schizophrenia, serotonergic overdrive targets the cerebral cortex, especially the anterior cingulate cortex and dorsolateral frontal lobe. This leads to two things [1]: overactivity of cytosolic phospholipse A2 linked to 5HT2A/2C receptors causes both cerebral and systemic deficiency of x-3 and x-6 phospholipids; and [2] excessive serotonin input into the cortex leads to a disruption of normal action potential generation by targeted neurons, which become hypometabolic. Because of loss of mutual reciprocal innervation between large areas of the cerebral cortex, denervation atrophy ensues; shrinkage of neuronal cell bodies and loss of neuropil account for the loss of grey matter which is the basis of brain atrophy in schizophrenia [4]. Normal dopamine input into an impaired anterior cingulated cortex causes positive symptoms and frontal lobe hibernation causes negative symptoms and cognitive impairment. The newer neuroleptics, in contrast to the older ones, can slow down the course of the disease because they block 5HT2A/2C receptors as well as dopamine receptors. They treat pathophysiology, not just symptoms. There is not room in this paper to repeat in detail the extensive literature review supporting this theory. The functional importance of the DRN-hippocampus loop cannot be demonstrated directly but must be inferred because schizophrenia is a disease which is unique to human beings and cannot be fully modeled in animals. DRN overdrive has been imaged by PET scan during mi-
1057
graine headaches; migraine, along with hypertension and metabolic syndrome (especially that seen in untreated schizophrenia), is posited to have a special relationship to schizophrenia [4,8]. This cluster of diseases, all of which are uniquely human, are hypothesized to share a similar pathophysiology involving the DRN-hippocampus loop [5]. DRN overdrive like that imaged during migraine attacks is hypothesized to occur with or without headache in all these diseases in response to stress. Excitotoxic cell death in the hippocampus is the second step of the pathophysiolgy, and aberrant disinhibited serotonergic function is the third step, the one that causes the various diseases. The pattern of dysfunctional serotonergic overdrive is different for each disease; genetic factors may relate to the ‘‘choice of disease’’. Hypothesis The excitoxicity in the hippocampus imaged in the Schobel paper is caused by stress-induced serotonergic overdrive passing from the DRN to the hippocampus via the entorhinal cortex. Discussion An excessive neuronal drive making its way through the hippocampal circuitry, from entorhinal cortex to dentate to CA3 to CA1 to subiculum, may not affect each subfield of the hippocampus equally. Mesial temporal sclerosis, which is thought to be caused by excessive epileptic discharges occurring, for example, in febrile convulsions in infants and young children, affects CA1 more than any other region of the hippocampus, as is the case with the Schobel mouse model and with schizophrenia [1,2,9]. The concordance between the three pathologies strengthens the excitotoxic interpretation of the two diseases. As mentioned above, CA1 pyramidal neurons express particularly high levels of both NMDA and AMPA receptors which may explain why it is particularly damaged as the excitotoxic train makes its way through hippocampal circuitry [3]. A purely genetic disease without environmental interplay will not have remissions and relapses. The relationship of stress to worsening in schizophrenia is the best documented environmental interplay in the disease. Brown and Birley interviewed 37 patients with onset of first episode schizophrenia and 13 patients with progression from mild to severe schizophrenia [10] They defined an ‘‘event’’ as one of any of a detailed list of possible major changes or crises in a person’s life, and found that, compared to controls from the general population, schizophrenics had an increased incidence of events (60% vs. 19%). Nuechterlein et al., proposed a ‘‘vulnerability/stress model of schizophrenic relapse’’ [11]. They studied relapse in patients compliant with medication compared to patients off medication. Medicated patients had a tenfold higher incidence of ‘‘independent life events’’ in the month prior to a relapse compared to months that did not precede a relapse. This pattern did not hold for patients off medication, which the authors interpreted as showing that medication raised the threshold for how stressful an event had to be in order to induce relapse. Increased stress, particularly crime-related and poverty-related stress, is a possible explanation for why people in lower socioeconomic brackets and migrant populations have a higher incidence of schizophrenia. It is true that many patients do seem to progress gradually into psychosis without a dramatic stressor; however, they may be hypersensitive to the small stressors of average everyday life. Remission Besides excitotoxicity, another part of the serotonin theory of schizophrenia is that healing of the hippocampus, primarily the
1058
A.E. Eggers / Medical Hypotheses 81 (2013) 1056–1058
dentate, can occur because of neurogenesis in the subgranular zone [4,5]. This is difficult but can occur, at least to an extent. Repopulation of the hippocampus restores the negative feedback loop and leads to symptomatic improvement. The hippocampus, including the granule cell layer of the dentate, has a rich distribution of S1 receptors, in contrast to S2 receptors, which are expressed relatively poorly in Ammon’s horn compared to neocortex and absent in the granule cell layer [12,13]. S2 receptors are associated with serotonin overdrive in the entorhinal cortex and frontal lobe and S1 receptors with healing in the dentate. Anti-depressants are thought to act via stimulating neurogenesis. Long-term lithium administration increases serotonin release in the hippocampus [14]. Anti-depressants and lithium might possibly be useful adjunct treatments in schizophrenia. Conflict of interest None. References [1] Schobel SA, Chaudhury NH, Khan UA, Paniagua B, Styner MA, et al. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron 2013;78:81–93. [2] Schobel SA, Lewandowski NM, Corcoran CM, Moore H, Brown T, et al. Differential targeting of the CA1 subfield of the hippocampal formation by
[3]
[4] [5]
[6] [7] [8] [9]
[10] [11]
[12]
[13] [14]
schizophrenia and related psychotic disorders. Arch Gen Psychiatry 2009;66:938–46. Coultrap SJ, Nixon KM, Alvestad RM, Valenzuela CF, Browning MB. Differential expression of NMDA receptor subunits and splice variants among the CA1, CA3, and dentate gyrus of the adult rat. Mol Brain Res 2005;135:104–11. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999;122:593–624. Eggers AE. Extending David Horrobin’s membrane phospholipid theory of schizophrenia: overactivity of cytosolic phospholipase A2 in the brain is caused by overdrive of coupled serotonergic 5HT2A/2C receptors in response to stress. Med Hypotheses 2012;79:740–3. Eggers AE. A serotonin hypothesis of schizophrenia. Med Hypotheses 2013;80:791–4. Nauta WJH. Hippocampal projections and related neural pathways to the midbrain in the cat. Brain 1958;81:319–40. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995;1:658–60. Mathern GW, Babb TL, Armstrong DL. Hippocampal sclerosis. In: Engel J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia, USA: Lippincott-Raven Publishers; 1997. p. 133–55. Brown GW, Birley JLT. Crises and life changes and the onset of schizophrenia. J Health Soc Behav 1968;9:203–14. Nuechterlein KH, Dawson ME, Ventura J, Gitlin M, Subotnik KL, et al. The vulnerability/stress model of schizophrenic relapse: a longitudinal study. Acta Psychiatr Scand 1994;89(Suppl. 382):58–64. Pompeiano M, Palacios JM, Mengod G. Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci 1992;12:440–53. Pompeiano M, Palacios JM, Mengod G. Distribution of the 5-HT2A and 5-HT2C receptors. Mol Brain Res 1994;23:163–78. Treiser SL, Cascio CS, O’Donohue TL, Thoa NB, Jacobowitz DM, et al. Lithium increases serotonin release and decreases serotonin receptors in the hippocampus. Science 1981;213:1529–31.