Disease and dendritic spines 25/4 Flashcards
How might dendritic spine pathology lead to congitive deficits?
- The formation, maintainence and dynamic nature of synapses and spines is underpinned by many proteins, which must be tightly controlled.
- Abberations in the function of these proteins can lead to having too many or too few dendritic spines.
- This has perturbing effects at the level of neural circuitry i.e., Lost synaptic connections and Altered glutamatergic / GABAergic connections
- Ultimately this can manifest as a cognitive deficit e.g., altered ability for learning and memory, altered personality, altered social interactions, altered motor behaviours.
This is one of number of mechanisms that may underlie cognitive deficits or brain function in general.
Examples of alterations in Dendritic spines pathology in disease
POST mortem studies (many years of disease, patients have been subject to many pharmacological alterations)
- Alzheimer’s disease shows an exaggeration on age related reduction in dendritic spines.
- Schizophrenia show reduction in number of spines compared to age matched controls.
- Autism show an increased number of dendritic spines.
It is important to consider that there is a difference as to whether alterations in spines result from the disease or contribute directly to disease pathology. This cannot be concluded from post mortem studies alone.
Examples of how dendritic spine morphology may be altered in pathology
Evidence for molecular underpinnings of dendritic spine alterations in autism.
Genetic mutations have been identified in several of the specialized post-synaptic density proteins, such as neuroglin/neurexin genes. These proteins have been shown to increase excitatory synapse number in hippocampal neurons. This supports the hypothesis that that synaptic dysfunction may be important in the etiology of ASDs.
Animal models with mutations in these genes show increase spine formation during development.
Evidence for molecular underpinnings of dendritic spine alterations in schizophrenia.
Polymorphisms in NRG1 are associated with schizophrenia. NRG1 regulates spine structure and function; long-term NRG1 treatment increases pyramidal neuronal spine density
How are dendritic spines altered in schizophrenia?
- Schizophrenia show reduction in number of spines compared to age matched controls. These reductions occur in two main regions: DLPFC and auditory cortex of superior temporal gyrus.
DLPFC also shows shows severe dysfunction in schizophrenia, as affected individuals show reduced activity of this region during cognitive tasks. Loss of spines are primarily in layer 3 - which undergoes hieghtened pruning in normal adolescent primate models.
Symptoms emerge during adolescence so may be associated with altered pruning mechanisms, alongside slight reduction of formation during childhood. For example, the increased loss in layer 3 may represent increased pruning in schizophrenia superimposed on normal levels of pruning.
How are dendritic spines altered in ASD?
Autism show an increased number of dendritic spines. Symtpoms emerge during early childhood, therefore it may be associated with an over-formation of synapses.
Spine density is inversely correlated with cognitive function - the higher the spine density, the lower the congitive function.
Such findings are consistent with an emerging hypothesis that the brains of individuals with ASD are characterized by hyperconnectivity in local circuits and hypoconnectivity between brain regions
How are dendritic spines altered in AD?
Alzheimer’s disease shows an exaggeration on age related reduction in dendritic spines. Loss of synpases may occur earlier than other pathological hallmarks. Dendritic and synaptic loss have a stronger correlation to cognitive impairment than tau or amyloid pathology.
What are the limitations of post-mortem associations between disease and dendritic dysmorphogenesis?
They do provided direct data of actual differences within patient brains, which cannot be obtained from animal models etc.
However:
the evidence is only correlatory.
The evidence may represent the combined effects of the disease alongside many pharmacological treatments.
Another problem is that post-mortem samples may represent endpoints of the disease, and therefore cannot discriminate between cause, consequence, compensation or confound.
They must be combined with genetic and neurobiological data in order to provide evidence for eitological causes and underlying molecular processes. It is also useful to correlate with behavioural data.
Define stem cells
‘An unspecialised cell characterised by the ability to self-renew by mitosis and the capacity to give rise to various specialised/differentiated cell types’
Define induced pluripotent stem cells
a type of pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell such as a keratinocyte, by inducing a “forced” expression of certain genes by exposing them to four transcription factors dubbed Yamanaka transcription factors. Importantly, iSPCs retain any mutations found in adult somatic cells. They can therefore provide a cellular model of a disease such as schizophrenia through inducing differentiation into neurons, which will faithfulyl recapitulate the complex genetic background of the patient and can be integrated with many other assays of the patient such as behavioural.
How have patient specific induced pluripotent stem cells been used to study schizophrenia?
One study (Brennand 2011) used patient specific induced pluripotent stem cells from five patients across the spectrum of schizophrenic disorders alongside 5 apparently healthy control.
They compared gene expression and found 600 genes differently expressed between patients and controls - only 25% were associated with schizophrenia.
They developed glutamatergic iPSCs and found overall reduced number of soma neurites, reduced expression of PSD95 archetypical post synaptic density protein) and reduced synaptic connectivity. However there was an inherent variability between all individuals.
However they found no alteration glutamatergic transmission.
Cellular treatment with one typical antipsychotic medication (loxapine) improved the number of synaptic connections. However this is no longer prescribed due to lack of efficacy!
