László SIKLÓS
scientific adviser

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Árpád PÁRDUCZ professor emeritus
Tibor HAJSZÁN senior research associate
Roland PATAI junior research associate
Tamás POLGÁR scientific administrator
Erika BÁNFINÉ RÁCZ laboratory assistant
Bernát NÓGRÁDI Szent-Györgyi student
Valéria MESZLÉNYI Szent-Györgyi student

NEURODEGENERATION AND NEUROPLASTICITY RESEARCH

Our group has discovered some basic mechanisms of both motoneuron disease and major depression. Using human samples from amyotrophic lateral sclerosis (ALS) patients, we have documented the lesion of neuro-muscular synapses and the disturbance of calcium homeostasis in motor neurons. We have also verified that similar alterations develop in animal models of ALS. Thus, results obtained from animal models may be extrapolated to human brain areas unavailable for direct studies. Similarly, we have performed pioneering experiments to develop and validate the synaptogenic hypothesis of depression. In human patients and in animal models of depression, we have documented a significant reduction of spine synapses in limbic brain areas, while antidepressant medication facilitated the formation of new synapses. We have also demonstrated that the severity of symptoms of depression is inversely proportional with the number spine synapses in the hippocampus.

To date, no attempted treatment lived up to expectations in ALS and in its animal models, only the anti-glutamatergic drug, Riluzol appears to be marginally effective. By our opinion, two major factors may contribute to the lack of success in neuroprotective trials. First, the reciprocal signalization between motor neurons and non-neuronal cells is not identified in sufficient detail. Second, the priority of destructive processes in remote neuro-muscular synapses versus perikaryal changes is still not resolved. As a result, our ongoing experiments attempt to characterize the neuron-microglia-astrocyte signalization processes and the alterations occurring at neuromuscular synapses by using animal models of motoneuron degeneration.

The major problem in successful treatment of depression is antidepressant resistance. As high as 60-70% of patients do not respond to the first-choice medication with selective serotonin reuptake inhibitor drugs. On the basis of our synaptogenic hypothesis, we assume that most antidepressants are unable to protect synapses against the destructive effects of stress, which might be the major cause of antidepressant resistance. Glutamatergic excitotoxicity appears to be the prime mediator of the stress-induced loss of synapses, offering a potential and promising therapeutic target. Our current work therefore aims at investigating whether anti-glutamatergic drugs and their analogues are capable of antagonizing the synaptolytic effect of stress and preventing the development of depression.

From methodological point of view, we expect breakthrough result from the implementation of a cutting edge technology in our laboratory. The electron microscopic tomography currently being mounted, will provide a powerful tool in the investigation of the 3-dimensional structures of central and peripheral synapses and their intracellular compartments, particularly mitochondria, which all play crucial roles in neurodegenerative processes and in psychiatric disorders. Furthermore, the technique will facilitate the 3-dimensional characterization of the distribution of immunogold labeled receptors in the synapses.

Milestone Publications

Kang, H.J. et al., (2012) Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nature Med., 18:1413-1419.

Hajszan T, Dow A, Warner-Schmidt JL, Szigeti-Buck K, Sallam NL, Parducz A, Leranth C, Duman RS (2009) Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression. Biol Psychiatry 65:392-400.

Beers, D.R., et al., (2006) Wild type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA, 103:16021-16026.

Beers, D.R., et al., (2001) Parvalbumin overexpression alters immune mediated increases in intracellular calcium, and delays disease onset in a transgenic model of familial amyotrophic lateral sclerosis. J. Neurochem., 79:499-509.

Siklós, L., et al. (1998) Intracellular calcium parallels motoneuron degeneration in SOD-1 mutant mice. J. Neuropathol. Exp. Neurol., 57:571-587.

Siklós, L., et al. (1996) Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann. Neurol., 39:203-216.

Dux, E., et al. (1987) Calcium in the mitochondria following brief ischemia of gerbil brain. Neurosci. Letters, 78:295-300.

Most Recent Manuscripts

Patai, R., et al., Calcium in the pathomechanism of amyotrophic lateral sclerosis – taking center stage? Biochem. Biophys. Res. Comm., in press.

Paizs, M., et al., Reduced calcium increase parallels shortened chemokine ligand 2 release in spinal motor neurons with upregulated parvalbumin along with a faster decline of neighboring microglial reaction after sciatic axotomy. CNS Neurol. Disord. Drug Targets, under revision.

Baka, J., et al., Remodeling of hippocampal spine synapses in a rat model of postpartum depression. Neuroscience, under revision.