May 2016

" as we know, there are known knowns; there are things we know we know.
We also know there are known unknowns;
that is to say we know there are some things we do not know.
But there are also unknown unknowns - the ones we don't know we don't know ".
Donald Rumsfeld, United States Secretary of Defense, briefing, 2002 ...
[ the same is true about schizophrenia - it remains a mystery ]

new but obscure
1. Schizophrenia hippocampal neurogenesis influences

a carer website

The developing views of a retired psychiatrist who looks after a family member who suffers from schizophrenia.
contact me if you want to help me out with my views, email : at email me! if not UK text to (44) ... UK to (0)7547 153 244

The Schizophrenia Brain :-

2006 was a crucial year

What causes schizophrenia? Nobody knows exactly what causes schizophrenia. This statement does not tell the whole truth.
In 2006 three academic papers were published in different academic journals.
Probably the authors were unaware of each other. Indeed probably no one read them all. The three papers are Now 1.
. - a paper
memory in schizophrenia: ..Al-asuri et al Testing the status of memory, by questionnaire, of all those patients in a community catchment area with continuing schizophrenia, . It confirmed the finding of a similar study on a different , comparable study population, some five years earlier. 80% have memory difficulties

In 2006 Reif et al 2006 - a study of three small cohorts of people: in depression, in a normal control group, in a group of continuing schizoprenia, who had died, and whose brains were preserved, so that the area of the brain known as the hippocampus, was available for post-mortem analysis, so as to be able to compare the status of a marker of neurogenesis in that area.
Only in the schizophrenia cohort was it found - that their hippocampus wa proliferating half only of the new cells that the normal and depression cohorts were delivering

Now 2015;- Allen KM, Fung SJ, Shannon Weickert C. Cell proliferation is reduced in the hippocampus in schizophrenia.

now - Nine years later, replicated and confirmed in this different group of people with schizophrenia.
Allen et al

[ If linking to the main Allen et al paper is difficult.. go to this Quote - from Allen et al - .

" We find a decrease in cell proliferation in the anterior hippocampus of people with schizophrenia, confirming the results of previous studies that have suggested a deficit in hippocampal cell proliferation and of neurogenesis in schizophrenia [ Reif et al ] in an independent cohort. Our results are consistent with those of Reif; however, we found a slightly larger decrease in Ki67 expression " ( i.e. 60% in the current study vs 50% in Reif et al ]
Now at last a known. .

People with continuing schizophrenia , compared to the rest of us, have around only half of the new cell presence in the dentate gyrus of the hippocampus in the brain. They deal with day to day matters with half of what is required - so they are liable to fail.

Later, a further study confirmed in humans, what was known for rodents, that the status of hippocampus new cell proliferation, taken in hippocampal tissue obtained during surgery for epilepsy,correlated with the memory status in those people from whom it was taken
Poor memory was correlated with those who had the reduced hippocampus new cell proliferation.
[ Coras ]

those who go on to continuing schizophrenia, do so because the hippocampus region in their brain - the gate-keeper between the inside and the outside world - has to manage this with only half the new cell provision to the hippocampal functioning that heathy people require to be available to be able to cope with all the changes in day to day living
- sorting out the wheat - necessary information,
from the chaff - ignore.

People with continuing schizophrenia will suffer from information overload

Information overload. Foerde et al a study of students at work taking forward a project whist their attention was taken away , distracted by surrounding matter of interest,

The hippocampal gate-keeping function - managing convergence between the inner stored experience, with what is going outside, using new cells in the hippocampus, to hold out irrelevant information, whilst allowing in useful experience - can't do that with only half the usual hippocampal new cell provisionSo, overload from too much incoming stimuli 'allows' some incoming stimuli, nomally ignored, to go directly, 'uncensored ' ,
to the striatal memory net work - normally used for procedural learning - habits - conversational grammar structure, bicycle riding.
In hippocampal stream, stored material can be consciouly sought: the striatal route is less flexible, less conscious, less accessible, where dopamine imprints salient value on what is passing through, using a different net work to consolidate what it has taken in.

Stand out material that gets into storage this way is abnormal, so brings anxiety with it, yet has to be dealt with,- given a narrative account - so becomes consolidated as an explanatory delusional system, normally segregated to allow some basic living to continue , but returned to when stress/anxiety persists unresolved.

next :- academic papers supporting loss of new cells in the dentate gyrus of the hippocampus
(1) year 2006 .Al-Usri et al
memory in schizophrenia: a clinical sample

Reif et al 2006
( hippocampal ) C a postmortem study in three hippocampal populations: a "depression" sample ...a normal sample ... a sample from continuing schizophrenia
For me this finding is enough to provide a plausible and complete account as to how continuing schizophrenia comes about .
Its cause !

a. more support
Das et al dental gyrus
This data suggest that the dentate gyrus is dysfunctional in schizophrenia, a feature that could contribute to declarative memory impairment in the disorder and possibly to psychosis, a conclusion consistent with the considerable molecular pathology in the dentate gyrus in schizophrenia

b.Stan et al
glutamate dental gyrus The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro.

[ How to reconcile this - Small et al = hipoocampus area Ca1 and subiculum are over excited
with Das et tamminga above. Das et al = Ca3 over excited.
Small et al, is on an early onset schizophrenia sample , Das et al, is on a sample of people with continuing , well established schizophrenia.

glutamate hyperactivity precedes overt schizophrenia It is succeeded by a hippocampal size reduction that persists


Pantelis [ Adelaide Australia ] at the third International Congress on Schizophrenia in Florence said - with colleagues in new data - they found
Ventricular enlargement correlated with illness duration in those already with established schizophrenia but did not appear in clinical high-risk subjects before psychosis ; rather, it occurred after schizophreniform first-episode psychosis appeared.

(5)Foerde et al
information overload

These findings, taken together with the cognitive failure and delusional expression occurring together as the illness first appears, strongly suggest the hippocampal loss of new cell performance occurs at the same time as these other happenings - at the onset of the illness, and persists afterwards, maintaining the illness.

( Benes Evidence for altered trisynaptic circuitry in schizophrenic hippocampus. Benes 1999 Inhibitory interneurons containing gaba live cell firing in the polymorphic layer send their processes to modulate excitatory cell firing. High resolution studies of the GABAA receptor have further suggested that a decrease of disinhibitory GABAergic activity (i.e., GABA-to-GABA) in stratum pyramidale of CA3 may coexist with reduced inhibitory modulation (i.e., GABA-to-excitatory pyramidal neuron) in the stratum oriens of this same sector. These changes could potentially involve excitotoxic damage to interneurons in CA2; but, the precise time frame for the induction of such an injury during pre- versus postnatal life cannot as yet be inferred from the available data
Taken from J Physiol 586.6 (2008) pp 1495-1502 K. A. Pelkey and C. J. McBain .. Benes mossy fibres
Target-cell-dependent plasticity within the MF-CA3 circuit
Mossy fibre axons (MFs) arising from dentate gyrus granule cells provide a major conduit for information flow from higher cortical areas into the intrinsic hippocampal circuitry by linking the entorhinal cortex with the CA3 hippocampus forming the second relay of the classic trisynaptic loop. Within the CA3 region individual MF axons provide excitatory glutamatergic input to both CA3 pyramidal cells (PYRs) and a diverse population of inhibitory interneurons. As inhibitory interneurons subsequently provide GABAergic inhibitory input to PYRs, MF-mediated monosynaptic excitation of PYR targets is accompanied by disynaptically mediated inhibition via the simultaneous recruitment of the feedforward inhibitory interneurons. In fact, at relatively low-frequency firing levels afferent throughput in the MF pathway is dominated by feedforward inhibition as MFs contact interneuron targets approximately 10 times more.
Where New cell proliferation in the hippocampus is reduced by 50%
the influence of dental gyrus inhibitory Gaba fibres is THEREFORE reduced, encoding what is salient from what is irrelevant, is unreliable. Noise is admitted. The glutaminergic area downstream is less inhibited, becomes overactive. Information input becomes an overload


Russ Poldrack, a neuroscientist at Stanford,
found that students learning information while multitasking causes their
schoolwork to go into the striatum, a region specialised for storing new procedures and skills, not facts and ideas.

Without the distraction of TV, the information goes into the hippocampus, where it is organised and categorised in a variety of ways, making it easier to retrieve.

Put the 2006 three studies together.

The brain in schizophrenia is handicapped under ordinary load circumstances. The reduced ability to achieve a normal level of continual new cells in the hippocampus means it cannot handle that level of incoming information.
Ordinary load is overload for schizophrenia.

That is why - as with the study of overload multi-tasking in normal students - the information coming into the schizophrenia brain is not able to be sorted out appropriately. In schizophrenia there is not enough hippocampus encoding of relevant stuff to update experience - nor can the hippocampus provide enough updating for continuing 'working memory', leading to cognitive failure to keep up, to move on in life. Irrelevant material gets into the striatal memory stream, achieving salience in the striatal procedural route- leading to a delusional system that gets a permanent status in long term memory.
Fewer new cells in the hippocamps leads to incoming information overload .

Salient material is drowned in too much non salient 'noise'. Some such material goes to the striatal memory stream where it is given dopamine approval. It is consolidated during sleep as with as procedural information It becomes a permanent sub-conscious delusional system, stored in its own compartment away from normal living coping systems, separate, taking over for context when incoming information is too stressful.......


[ " Richard Boyce and colleagues used an optogenetics technique that allowed them to use light to selectively silence neurons in the mouse hippocampus during REM sleep, inhibiting the signaling patterns called theta oscillations that are thought to be involved in learning and memory. Without disturbing the sleep of the animals, the researchers showed that inhibiting theta oscillations during REM sleep kept the mice from forming both contextual memories (such as the location of a new and interesting object) and emotional memories (such as the fear associated with receiving a mild foot shock). Disrupting these same oscillations outside of REM sleep, however, had no effect on these memories.Hippocampal theta, with a frequency range of 6-10 Hz, appears when a rat is engaged in active motor behavior such as walking or exploratory sniffing, and also REM sleep ]


Lars Schwabe and Oliver The Journal of Neuroscience, 8 August 2012, 32(32): 11042-11049; doi: 10.1523/JNEUROSCI.1484-12.2012 Abstract Learning and memory are supported by anatomically and functionally distinct systems. Recent research suggests that stress may alter the contributions of multiple memory systems to learning, yet the underlying mechanism in the human brain remains completely unknown. Using event-related functional magnetic resonance imaging, we asked in the present experiment whether stress may modulate the engagement of hippocampus-based "declarative" and striatum-based "procedural" memory systems during classification learning in humans and what brain mechanisms are involved in this effect. We found that stress reduced declarative knowledge about the learning task and changed the used learning strategy from a single-cue-based declarative strategy to a multicue-based procedural strategy, whereas learning performance per se remained unaffected by stress. Neuroimaging revealed that hippocampal activity correlated positively with task performance in the control condition, whereas striatal activity correlated with performance in the stress condition. After stress, hippocampal activity was reduced and even negatively correlated with learning performance. These findings show for the first time that stress alters the engagement of multiple memory systems in the human brain. Stress impaired the hippocampus-dependent system and allowed the striatum to control behavior. The shift toward "procedural" learning after stress appears to rescue task performance, whereas attempts to engage the "declarative" system disrupt performance .
see stress on memory

? How does the halving of hippocampal [ neurogenesis ]new cell proliferation come about?

Maybe perinatal birthing damage presages later reduced hippocampal stem cell proliferation in adolescent is how it happens ?

Look at these studies.
How does it come about that hippocampal new cell proliferation reduces at the age schizophrenia arrives

[ The studies support a helpful piece of advice - learn what is useful before adolesence when the illness arrives; It will then stay in memory. It will be difficult to learn after illness arrives

After stress, hippocampal activity was reduced and even negatively correlated with learning performance. These findings show for the first time that stress alters the engagement of multiple memory systems in the human brain. Stress impaired the hippocampus-dependent system and allowed the striatum to control behavior. The shift toward "procedural" learning after stress appears to rescue task performance, whereas attempts to engage the "declarative" system disrupt performance. Adolescence is a time when there can be stress - leaving family support. They have more coping experience in the protected environment of home. p
Stress reduces hippocampal new cell proliferation. [

Trauma and anoxia during human birth may do the same
Or maybe immune reaction to an infection at some crucial time in pregnancy interfere withthe way to new cell proliferation. No direct evidence but ....

November 2016
1. ED:- Is this adolescent pruning? McCarroll
In the blood, C4 complement binds to microbes to signal that they should be eaten by immune cells.

C4 has a second role in the brain.
C4 binds to neurons at the points where they connect with other neurons, and signals that these synapses, should also be engulfed by immune cells.

go to all Reference papers - with outline summary and Links to the Papers. Clinical high risk people - selected to be likely to go on to schizophrenia; of those that do proceed to clinical schizophrenia at that time, they show a new activity level in the hippocampal area of the brain -

1.Neuroanatomical abnormalities that predate the onset of psychosis: a multicenter study [ Mecheli
Archives General Psychiatry 2011 May;68(5):489-95 .
. but - particularly 2. Small et al glutamate hyperactivity precedes overt schizophrenia , is succeeded by a hippocampal size reduction that persists


Hippocampal stem cell proliferation is necessary for flexible memory usage.
This means to me

that it is

working memory failure , the cognitive failure that leads to schizophrenia sufferers not being able to move on with their lives from the age the illness arrives.
The delusional system will come from a different network and may - to me most likely - to involve the striatum dopamine line at some stage. Striatum dopamine applies permanence to a memory.

To be accounted for ....

... how is it that efficacious medications are all dopamine blockers ?
Dopamine is elevated in those who go on to get the disease.

What is it that allows a delusional system to develop ? And remains? The striatum is reciprocally connected to the hippocampus so would be involved in some kind of failure to do what the hippocampus normally does.

Karolinska on striatal NG 2015 - creating a neurogenesis cell line in the striatum

Suppose the same ? that leads to hippocampal neurogenesis reduction [ Reif et al } , affects SVZ neurogenesis too !?