How does hippocampal neurogenesis loss come about?
early damage: Late releaser effect
Possible explanation 1.
Intact neurobehavioral development but dramatic impairments of procedural-like memory following
early hippo rat lesion gives late adolescent memory problem
By analogy is this a possible and plausable explanation for the unaccounted 'sudden' clustering in humans of the onset of schizophrenia in adolescence and early adulthood. It perhaps explain the slightly later onset of the illness in women than in men.
[ ? They leave the nest better informed in personal and domestic care !? ]
It also accounts to some extent for the finding that schizophrenia is six times more likely in people who have epilepsy, and people with schizophrenia are more likely to have epilepsy. [ epilepsy and schizophrenia ]
Both have in common the vulnerability of the hippocampal area of the temporal lobe to damage - from low birth weight, from periods of hyoxia during birth ; from vertebral artery occlusion; from herniation of the upper brain through the tentorial tent because of pressure from oedema swelling above the tentorium within the enclosed resistant skull.
.... Forsyth et al
[ Of 125 survivors of severe perinatal brain damage, six (4.8%) later developed schizophrenia. ...
Jones PB, Rantakallio P, Hartikainen AL, Isohanni M, Sipila P. Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 north Finland general population birth cohort. Am J Psychiatry . 1998 Mar ; 155(3):355-64 ]
Obstetric abnormalities: schizophrenia
for and against
The work of O'Donnell [ Pharmacology & Therapeutics 133 (2012) 19-25 ] and others is particularly important here as this group has shown that neonatal hippocampal lesions impair dopaminergic innervation of the prefrontal cortex during adolescence. This is therefore direct evidence that an early postnatal intervention that is believed relevant to schizophrenia can induce late (adolescence) developmental alterations in DA ontogeny.
The explanation is that earlier hippocampal damage, usually around birth reduces subsequent hippocampal neurogenesis activity, but not enough to upset normal development in the years before adolescence - perhaps because the parents and the home shields them from the level of anxiety that comes after losing that social protection during and after adolescence.
The greater anxiety and stress [ Snyder ] during that period of leaving home during adolescense, further lowers hippocampal neurogenesis, the hippocampal roundabout connections being now weakened, allows the coming together of the world of schizophrenia
Now a new study ... IN Rats [ Lee et al :- Neuron. 2012 Aug 23;75(4):714-24. .... points to an intervention for those at riskk of deloping schizophrenia.
..... Early cognitive practice prevents adult deficits in a neuro-developmental schizophrenia model
[ abstract ]
Brain abnormalities acquired early, in perinatal life may cause schizophrenia like behaviour ( as it would be in rats ), characterized by adulthood onset of psychosis, affective flattening, and cognitive impairments.
Cognitive symptoms, like impaired cognitive control, are now recognized to be important treatment targets but current cognition-promoting programmes are ineffective.
' We hypothesized that cognitive training prior to the Rat adolescent period (of neuroplastic development)
can tune compromised neural circuits to develop in the service of adult cognition
and attenuate schizophrenia-related cognitive impairments that manifest in the ( RAT )adulthood '.
Concludes:- Adolescence appears to be a critical window during which prophylactic cognitive therapy may benefit people at risk of schizophrenia.
' We report, using neonatal ventral hippocampus lesion rats (NVHL), an established neurodevelopmental model of schizophrenia,
that early adolescent cognitive training prevented the adult cognitive control impairment in NVHL rats.
The early intervention also normalized general brain function [ indicated by success in tests other than on the one trained for )
[ .,. this confirms previous rodent studies showing that neonatal hippocampal damage leads to behaviour difficulties, but only after adolescence ; In between times they develop normally.
The jump to the clinical service is
.... if we can predict better who is going to become ill with schizophrenia, may be giving them more practical experience before the illness - perhaps in areas like shopping and cooking , domestic management, taking personal rsponsibility for money management , help them have a better life when the illness comes?
Possible explanation. 2.
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms, that have damaged the future abilities of the hippocampus.
Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus,
but the genes and molecular mechanisms accounting for this have been challenging to identify.
Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies.
In mice, C4 mediated synapse elimination during postnatal development.
These results implicate excessive complement activity in the development of schizophrenia.
It may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
the possible connection of immunity response to a cause of pruning, leading to schizophrenia
If immunity plays a part, might it lead to this new treatment
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