Tag Archives: learning disability

Psychiatric genetics: everything you need to know.

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Psychiatric geneticsPsychiatric genetics can be daunting for the non-expert. But it is so important for all mental health researchers and clinicians to have some understanding of where this field is at. Unlike much of the rest of psychiatric research and theory, modern genetics represents a firm foundation of valid and reliable knowledge. That knowledge is slowly unfurling how we think about psychiatric disorders such as ADHD, autism, depression, OCD, substance abuse, schizophrenia and bipolar.

A 2018 paper by Kendler and colleagues is an ideal overview, a straightforward, highly readable account of where things stand in psychiatric genetics, put in a historical context.

It has long been known that psychiatric illness runs in families. The heritability of psychiatric disorders (i.e. the degree of variance in a trait in a population which can be explained by genetics alone; a figure between 0 and 1) ranges from 0.3-0.4 for PTSD and depression, up to 0.7-0.8 for ADHD, autism, schizophrenia and bipolar. (Figure 1. Orange diagonal).

Psychiatric genetics

For the more genetic disorders (ADHD etc.) susceptibility very rarely comes down to one gene. Far more commonly, hundreds of individual genes are involved. Each gene, on its own, carries a tiny, almost negligible effect, at least in clinical if not statistical terms. But when a collection of risk genes is inherited, the chance of developing a psychiatric disorder starts to increase. For experts in psychiatric genetics, this is known as the polygenic risk score (PRS) the summed value of all the individual risk genes. The PRS is an important measure in modern psychiatric genetics.

Another important key-word is pleiotropy. This is when the same gene is involved in more than one psychiatric disorder. Pleiotropy has been recognized in psychiatry for some years. For example, a gene coding for a Ca2+ channel found on neurons, has long been known to constitute risk for a range of psychiatric disorders such as schizophrenia, bipolar, autism and major depression. Such knowledge is increasingly challenging the long-held view that there are discrete, neatly demarcated psychiatric disorders, as is found in the DSM and ICD classification systems.

Genetics researchers are now turning their attention to how a collection of genetic variants that increase the chances for one disorder (the polygenic risk score, PRS) may also increase the risk for other psychiatric disorders. This is pleiotropy at a higher level. The early findings again point to crossover between disorders. Kendler and colleagues elegantly illustrate the headline findings (Figure 1). The light blue squares show the genetic correlation between disorders using the methods of modern molecular genetics. The light orange squares show the genetic correlation between disorders using the more historical methods of family and twin studies.

For the present the main research effort will be to gather and pool more whole genome data from individual patients (and controls). Sample sizes of >100,000 will find more and more gene variants which confer risk for psychiatric disorders. Groups such as the multinational psychiatric genomics consortium (PGC) co-ordinate this task. Data-sets and computing resources are freely available to any researcher. Whether the traditional diagnostic systems collapse completely or remain in a different form cannot be know at present, but with modern molecular genetics, psychiatry is at last on a firm empirical and theoretical ground.

Cognitive disorders: the role of dendritic spines.

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Neuronal plasticity:

A major contribution of neuroscience to the humanities is the knowledge that the structure of the brain is moulded by the experiences the mind goes through – the phenomenon known as plasticity. It means that the circuits of the brain are sculpted by habitat, schooling, language, relationships, and culture, as well as by the unfolding genetic programme. The action occurs below the micrometre scale – at synapses (the points of connection between neurons) – and involves the exquisite choreography of a number of molecular machines. These molecular processes are so fundamental for cognition that their failure (whether driven by gene mutation or by harsh environments) results in neuropsychological disability. A major locus of plasticity (and hence, cognitive disability) is the dendritic spine.

pyramidal neuron

The dendrites of pyramidal neurons express thousands of dendritic spines. P=pyramidal neuron.

Principal neurons in the brain, such as cortical pyramidal neurons, express tens of thousands of small protruberances on their dendritic trees. These structures (dendritic spines) receive excitatory information from other neurons, and are highly dynamic. They can adjust their responsiveness to glutamate (the major excitatory neurotransmitter), becoming stronger (potentiation) or weaker (depression), as local circumstances dictate. This strengthening (LTP) or weakening (LTD) can be transient, or persist over long periods and as such, serves as an ideal substrate for learning and memory at synapses and in circuits. Potentiated spines increase in size, and express more AMPA glutamate receptors, whilst the opposite pattern occurs in synaptic depression to the extent that spines can be 'absorbed' back into the dendritic tree.

Over the course of childhood, dendritic spines (excitatory synapses) increase in number, but their numbers are 'pruned' back during adolescence to reach a plateau. Enriched environments have been shown to increase spine density, impoverished environments the opposite. In common psychiatric disorders, spine density is altered. For example, the most robust histological finding in schizophrenia is a reduction of spine density in the frontal cortex, auditory cortex and the hippocampus. In major depression, spines (and dendrites) are lost in the hippocampus. In autism, spine density actually increases. Finally, in Alzheimer's and other dementias there is a catastrophic, and progressive loss of cortical and sub-cortical spines.

Regulation of the spine:

The molecular biology of dendritic spines involves hundreds of proteins, but the outlines are now reasonably well understood. Scaffolding proteins [such as PSD95, shank(s), AKAP, stargazin and homer(s)] provide structural support and provide orientatation for membrane bound receptors, ion-channels and their downstream signalling pathways. The scaffold (post-synaptic density), facilitates effective signalling by ensuring that the correct protein partners are in close apposition. The scaffold is also tethered to proteins which bridge the synaptic cleft (cell adhesion molecules) and to bundles of actin filaments which provide the structure and force for spine enlargement (and retraction).

dendritic spine

Spine plasticity is fundamental for learning and memory. The shuttling of AMPA receptors underlies early phase plasticity. Modification of the actin cytoskeleton and local protein synthesis underlie long term plastic changes.

There is a constant remodelling of the actin cytoskeleton within the spine in response to synaptic and network signalling. Remodelling is via small, cytoplasmic G-proteins from the RHO family. Some family members promote the growth and stabilisation of actin filaments, whereas others promote actin disassembly. Mutations in the proteins which regulate actin dynamics are a cause of learning disability. Finally local protein synthesis (and degradation) occurs within dendritic spines, is tightly controlled and is essential for plasticity. Abnormalities in local protein synthesis within the spine underlie learning disability syndromes such as fragile X, neurofibromatosis and tuberous sclerosis.

Spine pathology:

Recent years have seen glutamate synapses move to centre stage in neuropsychiatry. This is not surprising given the role of pyramidal neurons (glutamate containing neurons) in information processing, and the role of glutamate transmission in learning and memory [see link]. But it is remarkable that so many psychological and cognitive disorders appear to 'coalesce' at dendritic spines.

The enclosed vector-graphic image [click here] highlights a selection of some of the proteins which are now known to be involved in autism, learning disability and schizoprenia.

Research will continue to decipher the complexity (and beauty) of the dendritic spine, but potential treatments are starting to emerge for disorders like fragile X, (which until recently were thought to be not amenable for drug treatment, as was the case for schizophrenia until the 1950s). Molecular neuroscientists will, almost certainly, continue to uncover more treatment targets. The task for psychiatry, as ever, is to keep abreast of neuroscience in all it's complexity (and beauty).