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Dr Cezar M Tigaret

Dr Cezar M Tigaret

Lecturer, Neuroscience & Mental Health Research Institiute

School of Medicine

Email
tigaretc@cardiff.ac.uk
Campuses
Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ

Overview

I aim to understand the causality between psychiatric risk factors and the emergence of symptoms and cognitive deficits in psychiatric illness, underpinned by alterations in neural synaptic and circuit functions.

Recent studies have found a complex genetic risk in psychiatric illnesses such as schizophrenia and bipolar disorder. These discoveries implicate alterations in the function of brain cells and how they communicate with each other, in the common symptoms found in psychoses. There is now an urgent need to translate these discoveries into more effective therapies based on causation.

I have a special interest in synaptic plasticity as a principal cellular mechanism of associative learning which forms the basis of our reasoning and capacity to represent and adapt to the environment and is disrupted in psychosis.

I combine state-of-the-art two-photon imaging and ex vivo slice electrophysiology in animal models and in silico modeling techniques.

Biography

Publications

2021

2018

2016

2015

2013

2011

2010

2009

2008

2006

2005

2003

1994

1992

1988

Synaptic and circuit consequences of genetic variation in voltage-gated calcium channels.

What?

Voltage-gated calcium channels (VGCCs) are proteins that convert the electrical activity of neurons into fast calcium signals subserving learning and memory and regulation of gene expression in the brain.

Why?

Genetic variation in voltage-gated calcium channel subunits, and in particular, in the CACNA1C gene encoding the CaV1.2 L-type voltage-gated calcium channels (CaV1.2 L-VGCCs) is strongly associated with risk for psychoses. Recent studies indicate that most risk-associated variants of CACNA1C act to reduce the levels of CaV1.2 L-VGCCs in the brain, but the causal links to psychiatric symptoms are poorly understood.

How?

I have developed a methodological framework to interrogate the synaptic, circuit, and behavioural impact of CACNA1C mutations, in collaboration with the groups led by Prof. Jeremy Hall and Dr. Kerrie Thomas at NMHRI, and Prof. Matt W. Jones (University of Bristol). The research is aligned with the "Mind, brain and neuroscience" research theme at the College of Biomedical and Life Sciences, and integrates state-of-the-art two-photon imaging and electrophysiology with behavioural analyses.

Outcomes.

The study, published in Molecular Psychiatry in 2021, is the first to show pathway-selective deficits in Hebbian synaptic plasticity and circuit synchronization in the hippocampus, and altered hippocampal-dependent associative learning in Cacna1c+/- animals.

This study also demonstrates for the first time the rescue of neurobiological and behavioural phenotypes associated with Cacna1c haploinsufficiency using a drug with neurotrophin BDNF mimetic activity in vivo.

What next?

In 2021 I was awarded a 3-year MRC Research Grant as a sole PI, to interrogate the potential of cholinergic muscarinic and Ca2+-sensitive K+ channel drugs to rescue the consequences of reduced CaV1.2 dosage on synaptic plasticity and integration of synaptic input in neurons.

I collaborate with Prof. Frank Sengpiel (School of Biosciences) to investigate synaptic consequences of Cacna1c gain-of-function mutations in animal models of Timothy syndrome.