Psychiatric illness ‘explained’: Disorders of CNS Connectivity

The power of the nervous system:


The astonishing power of the nervous system does not reside in a single neuron. (That said, an advanced supercomputer is required for the task of modelling the processing power of even a single neuron).

Nervous tissue is immensely powerful because of the rich connectivity between neurons. A 1mm voxel of cerebral cortex (a standard fMRI unit), contains ~300 million synaptic connections and ~50 thousand neurons [ref].  Scaled up to the whole human brain, there are estimated to be several hundred trillion synaptic connections within a total pool of ~100 billion neurons. Neuronal networks are the foundation of, perception, movement, thinking, memory and the personality.

Network learning

A crucial property of neuronal networks is that they learn from experience. Experience may stem from the external world (sensation) or the inner world. Learning is achieved by adjusting the strength of the connections between neurons. New connections can form, and weak connections wither away – essentially a process of re-wiring. Taking up a musical instrument or a new language, for example, constitutes a major re-wiring exercise, although higher, more mysterious faculties – such as selfhood, agency and individual identity – are already wired-up in infancy, and remain a foundation throughout life, except if threatened by the most severe psychiatric disorders.

Alzheimer’s disease is the prototypical example of a network illness. Progressive       shrivelling of the network mirrors the decline of the faculties, from initial problems with memory right up to the disintegration of selfhood.

Network health

Network health is vital for mental health. The stabilisation of essential connections, the formation of new connections and the controlled elimination of redundant connections involves many components.

  • There are components which span the gap between nerve terminals and dendritic spines to ensure that connections remain tightly bound [link].
  • There are signalling pathways which control the dynamic, flexible actin scaffold which give terminals and spines their anatomical structure.
  • There is, ready-to-hand, protein-synthesis machinery for making additional spines as learning proceeds.
  • Finally, and most recently explored, there are mechanisms for ‘clearing up’ the debris when connections are no longer required. Such components (microglia, complement proteins) are much more familiar in their role as immune cells and immune signals, but their role extends beyond inflammation. Microglia and complement are now recognised as key components in the wiring of the brain as it learns and develops.

Major psychiatric illness

dendritic spine

Where those components involved in the function and structure of synaptic connections are defective, psychiatric illness can result. Mutations in the components which bind the nerve terminal and dendritic spine are a cause of autism. The cause of many learning disability cases, hitherto unknown, are mutations in proteins which control the actin scaffold. The psychiatric manifestations of Fragile X syndrome (intellectual deficits / autistic features / hyperactivity) result from abnormal protein synthesis in dendritic spines and subsequent abnormal local wiring.


Microglia & complement proteins

pink-eatme-cake-topperThe latest components to receive attention, as pertains to psychiatric illness are the microglia and their signalling pathways, specifically complement proteins.

Complement proteins function as a tag, essentially an ‘eat-me’ signal, on synapses destined for elimination. The tag is recognised by the phagocytic microglia which engulf and clear the redundant synaptic elements [link].

Although the role of immune components in psychiatric illness has become a hot topic, many researchers are still accustomed to regard microglia and complement in the context of inflammation rather than CNS re-wiring. Both major depression and schizophrenia, have been linked with abnormal immune components, but neither disorder is inflammatory in the same sense as encephalitis or meningitis. The main histological finding in schizophrenia is decreased connectivity between neurons, not inflamed nervous tissue. Similarly, an anatomical correlate of depression is impoverished connectivity in the hippocampus, not inflammation.

A major development in Alzheimer’s research has been the recognition of up-regulated complement proteins and microglial phagocytosis commensurate with the loss of neuronal connections. The crucial observation is that such changes occur prior to amyloid deposition and tangle formation [link]. Alzheimer’s appears to be a disorder of runaway synaptic loss. Drug discovery efforts are aimed at blocking complement protein receptors to protect synapses [link].

Schizophrenia has been associated with changes in the genes coding for a specific complement protein (C4A). Knockout of the C4A gene in an animal model causes a marked alteration in the pruning of synaptic connections in later life [link]. Schizophrenia, albeit to a far less extent than Alzheimer’s, is regarded as a disorder of impoverished connectivity, (whereas Autism is associated with increased dendritic spines and increased connectivity) [link].

Hold on –  what about the ‘dominant’ wet-ware hypotheses?


An older generation of psychiatric researchers may ask where dopamine [link]] and perhaps glutamate [link] fit into a model of psychiatric illness in which abnormal connectivity between neurons appears to carry robust explanatory power. Earlier models posited that an excess or deficiency of neurotransmitter or receptors lay at the root of major depression and schizophrenia. Such models stemmed from the relatively primitive knowledge of the synapse available at the time (circa 1965-1975). Then, the hot topics in neuroscience were; the nature of neurotransmitter release (Sir Bernard Katz, UCL) and the ‘visualisation’ of receptors (Solomon Snyder, John Hopkins).

The answer (to the question of how glutamate and dopamine are accommodated) is fairly straightforward: Glutamate (finally admitted to the neurotransmitter club circa 1983-87) is the fast neurotransmitter between nerve terminals and dendritic spines, throughout nervous tissue. Dopamine determines the strength of the connection between the glutamate terminal and the dendritic spine within specific CNS structures. Dopamine functions as a teaching signal; adjusting connectivity and promoting learning in higher centres.

Frontier psychiatry


The obvious strategy of searching for molecules which can impact on connectivity is well underway.

That said, existing psychiatric treatments, such as antidepressants, lithium and dopamine antipsychotics have an impact upon connectivity to the extent that structural changes can already be detected, albeit in a population of patients rather than the individual, with routine MRI scans. Drugs impact upon plasticity: Drugs impact upon CNS structure.

A more basic question goes back to the very roots of modern psychiatry. The question is whether, for some, the neuronal networks are destined to be unwell from the outset (endogenous psychiatric illness), or if, for others, adverse experiences during development cause the network to wire-up pathologically (exogenous psychiatric illness). Then again, there is the third position, in which the choreography between the neuronal hardware and the external environment determines who will succumb to psychiatric syndromes. Whatever the proximal cause(s), endogenous or exogenous, major psychiatric illness appears to stem from abnormal connectivity within neuronal networks.

Ketamine for resistant depression: Outstanding promise, outstanding issues.

Outstanding Promise.

Ketamine has been around for many years, firstly as a dissociative anaesthetic and then as a psychedelic drug. But it might become best known for it's powerful antidepressant properties (Berman et al 2000; Zarate et al 2006). Compared to existing antidepressants, which take around 2 weeks to work, ketamine exerts a large antidepressant effect on the first day of treatment.

depression ketamine murrough

Figure 1: The antidepressant effect of ketamine over 6 treatment sessions. The improvement on day 1 (measured using the MADRAS scale) was predictive of the response achieved following the sixth treatment session.

The robust antidepressant effect of ketamine also occurs in patients who have not found relief with existing drugs or with ECT. In the latest study to be reported, 24 patients with treatment-resistant depression underwent up to 6 sessions of intravenous ketamine (0.5mg/Kg in 40 mins) over ~2 weeks. Over 70% of patients responded to ketamine, and the overall reduction in depression was large and rapid (Murrough et al 2013) (Figure 1).

Outstanding Issues.

To date a major issue has been the lack of persistence of the antidepressant effect. In previous studies, involving a single ketamine treatment, depression returned within one week of the session or less. In the study by Murrough et al, this was extended to an average of 18 days. This is an improvement, but further work will be needed to solve the problem of the relatively short-lived antidepressant effect of ketamine.

An understanding of the mechanism by which ketamine alleviates depression may be necessary if we are to extend the duration of it's beneficial effects. Pre-clinical work suggests that ketamine boosts the health and integrity of synapses and neuronal networks. Much of the action is believed to take place within dendritic spines, and involves local protein synthesis (Duman et al 2012) (Figure2).

ketamine mechanism

Figure 2: The antidepressant effects of ketamine may depend upon activation of mTOR and local protein synthesis in dendritic spines.

Two molecules of relevance are mTOR and GSK-3. Ketamine enhances local protein synthesis by activating mTOR and by inhibiting GSK-3. [GSK-3 inhibits mTOR]. A drug, such as lithium, which inhibits GSK-3 might enhance the antidepressant effect of ketamine. This has now been demonstrated in pre-clinical studies (Liu et al 2013). The clinical question, which will now be addressed in trials is whether lithium treatment extends and enhances the antidepressant effects of ketamine. Lithium has been used for treatment-resistant depression for many years, and has a good evidence base (Bauer et al 2010) so that the combination of ketamine and lithium presents as an interesting and relatively straightforward strategy for stubborn depression.

However it is somewhat odd that the proposed mechanism for ketamine involves new protein synthesis and synaptogenesis (which take time, and are sustained) whereas the clinical effects of ketamine are very rapid (and transient). Other mechanisms may have more explanatory power. For instance a recent fMRI study showed that ketamine decreased the connectivity of limbic and prefrontal regions which are known to be overactive in depression (Scheidegger et al 2012). More provocatively, it appears that the antidepressant effect of ketamine depends upon the extent of the acute psychological reaction produced by the drug. Although the dissociative/psychedelic properties of ketamine are sometimes regarded as unwanted “side-effects”, a recent paper showed that the acute psychedelic and subsequent antidepressant effects are related (Sos et al 2013).

Cognitive disorders: the role of dendritic spines.

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).