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Frenguelli Lab

Research Leader: Bruno Frenguelli

The Effects of Metabolic Stress on Neuronal Function

The mammalian brain is exquisitely sensitive to reductions in the supply of oxygen (hypoxia) and glucose (hypoglycemia). The large number of incidents during which one or other or both (ischemia) can occur (stroke, heart attack, head injury, near-drowning, carbon monoxide poisoning, hypoglycemia, epileptic seizures) indicates the scale of the problem. Intense efforts are being made to investigate the sequence of cellular and molecular events that are initiated by cerebral hypoxic/ischemic episodes with a view to providing better treatments.

Our laboratory is especially interested in the effects of hypoxia and ischemia on synaptic transmission in the mammalian hippocampus. The hippocampus is a region of the brain critically involved in certain forms of learning and memory, but, paradoxically, is one of the most vulnerable regions of the brain to hypoxia/ischemia. There are many human clinical cases studies in which cerebral ischemia is associated with profound anterograde amnesia and selective pathology of the hippocampus, in particular of CA1 pyramidal neurones.

To investigate the neuronal response to hypoxia/ischemia we use a combination of electrophysiological, pharmacological, biochemical, biosensor and imaging techniques.


Helping the brain help itself

ATP (adenosine triphosphate) is the primary source of both cellular energy and the neuroactive metabolite adenosine. The breakdown of ATP during metabolic and traumatic stress results in the release of adenosine into the extracellular space. This has the beneficial effects of reducing neuronal activity (which would otherwise consume ATP) and dilates blood vessels in the brain, increasing the supply of nutrients. However, whilst this is beneficial to the brain in the short term, adenosine and its metabolites inosine, hypoxanthine and xanthine can be lost from the brain into the general circulation. This is troublesome since the brain requires hypoxanthine to make ATP via the purine salvage pathway The loss of these metabolites to the systemic circulation likely explains the slow recovery of ATP levels in the injured brain. This would limit both the capacity of the brain to activate reparative processes and reduces the size of the adenosine reservoir, with implications for the development of post-injury seizure activity and the eventual recovery of the brain.

We have recently shown that brain slices, which are known to have reduced ATP levels due to the ischemia and physical trauma associated with their preparation, can have their ATP levels increased to close to in vivo values. This is done by the simple addition of D-ribose and adenine (“RibAde”) to their incubation solution. D-ribose provides the sugar backbone of ATP, whilst adenine provides the nucleobase to which D-ribose is attached. Subsequent actions of a number of purine salvage enzymes convert the D-ribose and adenine into ATP. This process is more energy efficient compared to the de novo formation of ATP and is the dominant mechanism by which the brain makes ATP.


The improved tissue content of ATP has a number of functional consequences: the increased cellular ATP results in a larger reservoir of adenosine which can be released in response to physiological and pathological stimulation. Increased release of adenosine during high frequency (theta burst) stimulation raises the threshold for the induction of long-term potentiation (LTP), whilst during brief oxygen/glucose deprivation (OGD), increased adenosine is released which accelerates the inhibition of synaptic transmission and delays its recovery on reoxygenation. Furthermore, application of RibAde after OGD in cultured neurones reduced cell death. These data, plus the fact that D-ribose and adenine are well tolerated by humans, suggest that RibAde may be useful in patients having suffered from some form of brain injury.

Synaptic Plasticity in the Hippocampus

Long-Term Potentiation and learning and memory

hippo gif

Synaptic plasticity is a process by which the strength of communication between neurones can be increased or decreased. Synaptic plasticity is believed to underlie the storage and recall of information, in other words, learning and memory. At present, the best cellular model for synaptic plasticity is long-term potentiation (LTP), a phenomenon that possesses many of the properties associated with learning and memory in mammals. A great deal of research has been undertaken on LTP in the hippocampus, a region of the brain (left; shown in red) especially involved in certain types of learning and memory. The hippocampus is affected in many types of insults to the brain and is one of the first brain regions to be damaged during the progress of Alzheimer’s disease and likely results in the forgetfulness of patients suffering from the early stages of Alzheimer’s.

Experience-dependent synaptic plasticity and the role of MSK1

Long-term changes in neuronal function underlie the behavioural and cognitive response to experience. Some of these experiences promote the rapid and persistent encoding of information and can have valuable repercussions – for example the association of illness or death (of others!) with poisonous plants or animals, in order to avoid them in future. On a more mundane level, such associations allow us to remember where we left our house key, mobile phone or that we have an appointment to keep or a lecture to go to. However, sensory experiences can occur over prolonged periods – consider learning to read or write or play a musical instrument. In both these cases of rapid and protracted acquisition, long-term storage or adaptation requires changes at the genomic level to provide the proteins necessary to hard wire these experiences. As such, the genomic changes, and the mechanisms by which they are induced have been the subject of considerable investigation.

We have been examining the contribution of a protein kinase – MSK1 – to experience and protracted activity-dependent synaptic plasticity. MSK1 is interesting as it is activated by BDNF, a key growth factor in the brain implicated in a range of processes from brain development to learning and memory. Moreover, MSK1 exerts is actions via influencing gene transcription through the phosphorylation of the transcription factor CREB and the chromatin-associated histone H3. Accordingly, MSK1 is well-placed to transduce the effects of BDNF into long-lasting changes in neuronal structure and function.

We have shown that MSK1 is necessary for the regulation of synaptic strength in response to prolonged inactivation of synapses caused by blocking voltage-gated sodium channels with TTX. Moreover, MSK1 is also necessary for the enhancement of synaptic transmission associated with environmental enrichment, in which rodents are raised in an environment providing them with additional social and sensory stimulation through the provision of larger numbers of cage-mates, ladders, rope swings, tubes and exercise wheels. Current studies are investigating the genomic, molecular, cellular and behavioural consequences of enrichment and the role of MSK1, from birth to old age.

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