Mechanisms of schizophrenia

It took me a while to figure out whether to divide this article into two parts or to sum up everything in one long, possibly tedious reading. Honestly, I still don’t know, so I’ll just start writing and we shall see what it turns out to be.

I’m sure you’ve all heard of schizophrenia – the disease of thought disorder, or know people who suffer from it. But only a few actually understand what it is about.

No wonder scientists have been struggling to develop efficient treatments for schizophrenia; not only is it largely uncommon (1% of the world’s population is affected), but also its causes are usually unknown. Scientists generally refer to schizophrenia as a psychiatric disease involving a progressive decline in functioning, which begins in early adolescence and persist throughout the patient‚Äôs life. Due to its heterogenous symptoms and multiple possible causes, there are many hypotheses that intend to explain what triggers schizophrenia and how it develops.

In spite of the fact that is it a genetic disorder, the environment and external factors (such as viral infections during the intrauterine and infant period) may be crucial to the development of schizophrenia. The symptoms have been divided¬†into two categories. The positive symptoms include thought disorder, hallucinations, delusions, disorganised speech etc., whereas the negative symptoms are characterised by poverty of speech, reduced expression or emotion, memory impairment, anergia, abulia etc. In addition, the brains of schizophrenics show structural macroscopic abnormalities (for instance, the enlarged ventricles and the shrinkage of the surrounding brain tissue), as well as microscopic changes, such as the dysregulation of dysbindin gene in the formation of abnormal dendritic filopodia. There are three types of schizophrenia, according to its symptoms:¬†paranoid schizophrenia – auditory¬†hallucinations, delusions, strong belief of being chased¬†by powerful people;¬†disorganized schizophrenia –¬†reduced emotions and lack of emotional expressions, incoherent speech (mostly negative symptoms);¬†catatonic schizophrenia –¬†impairment of movement, usually immobility and catatonia, bizarre grimacing (this is similar some of the symptoms of¬†hysteria,¬†which has been¬†described as a sexually related and later on, as¬†a psychiatric disorder up until the beginning of the 20th century).

But enough with the boring general details! Let’s get to the fun part:¬†The monoamine¬†hypothesis¬†of schizophrenia!¬†Here we are going to talk about two very important neurotransmitters in the central nervous system: dopamine and glutamate. The second one is the main excitatory neurotransmitter in the brain. There are four main types of glutamate receptors: AMPA, NMDA, kainate and mGluRs. It has been demonstrated that reduced activity of the NMDA receptors can result in some of the negative symptoms of schizophrenia (lack of social behaviour, catatonia).

Dopamine is the metabolic precursor of another neurotransmitter, noradrenaline (norepinephrine). But¬†there is a lot more to dopamine and its roles in the brain than this. There are four main dopaminergic pathways: the mesolimbic pathway –¬†related to the “reward” system and significance; it has its roots in the ventral tegmental area and projects to the nucleus accumbens (in the ventral striatum) and the limbic system;¬†the mesocortical pathway –¬†involved in cognition and motivation;¬†the tuberoinfundibular pathway –¬†roles in lactation; these dopamine neurones originate in the hypothalamus; the nigrostrial pathway –¬†involved in movement planning and connects the substantia nigra (midbrain) to the striatum.

Schizophrenia and another mental illness, a neurodegenerative one, Parkinson’s disease, are also linked to dopamine. When it comes to schizophrenia, it seems that the mesocorticolimbic pathways have more influence on its onset:¬†the ‚Äėpositive‚Äô symptoms appear to be triggered by dopaminergic hyperactivity in the mesocorticolimbic system. At the same time,¬†hypoactivity of dopamine is this region is the cause of ‚Äėnegative‚Äô symptoms. Nevertheless, it has been discovered that¬†overexpression of the dopamine receptor D2 (DRD2) gene in the¬†striatum also reduces motivational behaviour in mice, therefore mimicking psychotic ‚Äėnegative‚Äô symptoms. Similar findings show that increased density of dopamine D2 receptor in the striatum, along with lower thalamic density of this receptor appear to induce divergent thinking, which is associated with schizophrenia. ¬†

All these changes may account for the abnormalities that we see in¬†“mad” people. It seems that we are so fragile, given that¬†often small chemical and physical disruptions can trigger something as¬†big and terrifying as schizophrenia. Imagine hearing, seeing, feeling, smelling things everyone says are not real (schizophrenics often have multiple hallucinations: auditory, visual, gustatory, tactile, olfactory). But to you they are so real and disturbing!¬†Many¬†schizophrenics even hear their own thoughts as if they are coming from the outside and therefore believe that everyone knows what’s in their heads. Imagine having the constant feeling that someone is after you (paranoia) or being certain¬†that¬†you are dead (the Cotard’s Syndrome) or that your husband has an affair (the Othello Syndrome).

I think this topic can never be fully covered and we would spend days talking about schizophrenia, so this article should better come to an end. As I am sure you have lots of questions and comments, don’t be shy and post anything you think it’s relevant to what has been discussed above. Hope you enjoyed this reading.

For further information: 

Bear et al., 2006. Neuroscience – Exploring the Brain. s.l.:Lippincott Williams & Wilknins, pp. 679-684

de Manzano et al., 2010. Thinking Outside a Less Intact Box; Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Insividuals. Public Library of Science

Jia et al.,  2014. The Schizophrenia Susceptibility Gene Dysbindin Regulates Dendritic Spine Dynamics. The Journal of Neuroscience, Oct.pp. 34-41

Kandel et al., 2011. Modeling Motivational Deficits in Mouse Models of Schizophrenia: Behavior Analysis as a Guide for Neuroscience. Behavior Processes, pp. 149-156

Kolb et al., 1996. Fundamentals of Human Neuropsychology. 4th Edition ed. s.l.:W.H. Freeman and Company

Image by Damaris Pop

Smells, learning and memory

After seeing this article’s title, you might have thought: “That sounds rather boring. I mean, what is so interesting about the nose?” Perhaps the “memory” part aroused your curiosity, though. If that’s so, you might find the following reading worth having a look at, as you could discover some surprising things about the “nose”.

I’d like to begin by emphasising something important: we don’t actually smell with our noses; it’s the brain that identifies different odours through the central olfactory pathways, but we’ll get to that soon. What does happen in our nasal cavity is the activation of the olfactory receptors (a type of neurone) of the primary olfactory system, by chemical stimuli¬†called¬†odourants. The binding of odourants to the olfactory receptors’ cilia triggers the transduction process, which involves G-protein stimulation, formation of the cyclic AMP (cAMP) and membrane depolarisation, by the opening of ion channels (calcium, sodium and chloride). This complex signalling cascade results in a receptor potential which is then coded as an action potential (provided the receptor potential reaches a certain threshold) and then transmitted further along the receptor’s axons (remember, they are actually neurones!) The axons form the olfactory nerve, but they also group in small clusters and converge onto the two olfactory bulbs, in spherical structures known as glomeruli. Here, the axons synapse upon second-order neurones which form the olfactory tracts and finally project to the olfactory cortex (involved in the perception of smell) and to some structures in the temporal lobes, the medial dorsal nucleus (in the thalamus) and the orbitofrontal cortex. The last two are thought to play an important role in the conscious perception of smells. A pretty intricate process, isn’t it? But it is¬†a lot more to olfaction than this!

Running parallel to the primary olfactory system is the accessory olfactory system. This has been shown to detect our favourite smelling chemicals, the pheromones. As I am sure most of you are aware of, pheromones are involved in reproductive behaviours, identifying individuals, aggression and submission recognition. Not only the type of chemical stimuli, but also the structures in the accessory olfactory system are different: the vomeronasal organ in the nasal cavity, the accessory olfactory bulb and last but not least the hypothalamus and amygdala (and hippocampus) as the final axonal targets. The amygdala and hippocampus are known for their implications in emotions and long-term memories (check out article about memory). Thus, olfaction also plays an important role in the integration of different odours in emotion processes, as well as explicit memory and associative meanings to odours.

Interestingly, each receptor cell is defined by only one receptor protein, which is encoded by a single receptor gene. These genes form the largest family of mammalian genes: 1000 in rodents, 350 in humans. The receptor cells have unique structures and are divided into different types according to their sensitivity to odours: each receptor type is activated by a single odour; nevertheless, one odour can activate many receptor types and the combination as well as the frequency, rhythmicity and temporal pattern of receptor stimulations encode for odour information.

Studies in Drosophila have shown another very important function of the olfactory processes: the associative learning. Gustatory unconditional and odour conditional signals both converge on the antennal lobe and mushroom body of the Drosophila, establishing learning efficacy of appetitive and aversive memories in classical conditioning. The release of certain catecholaminergic neurotransmitters such as dopamine and octopamine (the insect analogue of noradrenaline) are involved in the aversive and appetitive behaviours, respectively. In an incredibly revealing study, Lee Chi-Yu and his colleagues developed this topic in much more detail. I strongly recommend you have a look at it here.

As you might have guessed, given the fact that olfaction has a wide range of implications, its impairments are present in different mental diseases. Olfaction deficits or absence (anosmia) have been identified in Alzheimer’s disease and dementia, whereas olfactory hallucinations and weird smells are one of the main symptoms of schizophrenia.

Hopefully, you didn’t find this article too long or confusing. Did you find out new information about olfaction? If you have any questions or comments, please feel free to upload your¬†posts. I’m looking forward to them as always.

For further information:

Bear et al., “Neuroscience”, third edition, Lippincott Williams & Wilkins

My friend’s article

Another very relevant article

Photo by Isuru Priyaranga