Summary: Researchers identified specific receptors for acetylcholine that reroute information flow through memory circuits in the hippocampus. The findings could have implications for the development of drugs to help enhance or protect memory from diseases associated with cognitive decline.

Source: University of Bristol

Bristol-led research has identified specific drug targets within the neural circuits that encode memories, paving the way for significant advances in the treatment of a broad spectrum of brain disorders.

Loss of memory is a core feature of many neurological and psychiatric disorders including Alzheimer’s disease and schizophrenia. Current treatment options for memory loss are very limited and the search for safe and effective drug therapies has, until now, had limited success.

The research was done in collaboration with colleagues at the international biopharmaceutical company Sosei Heptares. The findings, published in Nature Communications, identify specific receptors for the neurotransmitter acetylcholine that re-route information flowing through memory circuits in the hippocampus.

Acetylcholine is released in the brain during learning and is critical for the acquisition of new memories. Until now, the only effective treatment for the symptoms of cognitive or memory impairment seen in diseases such as Alzheimer’s is using drugs that broadly boost acetylcholine. However, this leads to multiple adverse side effects.

The discovery of specific receptor targets that have the potential to provide the positive effects whilst avoiding the negative ones is promising.

Current treatment options for memory loss are very limited and the search for safe and effective drug therapies has, until now, had limited success. Image is in the public domain

Lead author, Professor Jack Mellor, from the University of Bristol’s Centre for Synaptic Plasticity, said: “These findings are about the fundamental processes that occur in the brain during the encoding of memory and how they may be regulated by brain state or drugs targeting specific receptor proteins.

“In the long-term, the discovery of these specific targets opens up avenues and opportunities for the development of new treatments for the symptoms of Alzheimer’s disease and other conditions with prominent cognitive impairments. The academic-industry partnership is important for these discoveries and we hope to continue working together on these projects.”

Dr Miles Congreve, Chief Scientific Officer at Sosei Heptares, added: “These important studies have helped us to design and select new, exquisitely targeted therapeutic agents that mimic the effects of acetylcholine at specific muscarinic receptors, without triggering the unwanted side effects of earlier and less-well targeted treatments. This approach has the exciting potential to improve memory and cognitive function in patients with Alzheimer’s and other neurological diseases.”

“It is fascinating how the brain prioritises different bits of information, working out what is important to encode in memory and what can be discarded. We know there must be mechanisms to pull out the things that are important to us but we know very little about how these processes work. Our future programme of work aims to reveal how the brain does this using acetylcholine in tandem with other neurotransmitters such as dopamine, serotonin and noradrenaline,” said Professor Mellor.

About this memory research news

Author: Shona East
Source: University of Bristol
Contact: Shona East – University of Bristol
Image: The image is in the public domain

Original Research: Open access.
“Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits” by Jon Palacios-Filardo, Matt Udakis, Giles A. Brown, Benjamin G. Tehan, Miles S. Congreve, Pradeep J. Nathan, Alastair J. H. Brown & Jack R. Mellor. Nature Communications


Abstract

See also

This shows a brain and a desk lamp

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations.

An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3.

Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1.

However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs.

Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively.

Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.



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