Biological Basis of Neuropsychiatric Disorders

Joyeeta Dutta

Apr 17, 2002. Biological Basis of Neuropsychiatric Disorders

Hypothesis M-currents (a slow, voltage-dependent, muscarinic K+ current) can modulate the physiological correlates of synaptic competition in the hippocampus, thereby controlling runaway excitation and subsequent consolidation of synchronous neuronal network populations that lead to epileptogenesis.

Specific Aims Aim 1: To establish synaptic competition, i.e. near coincident firing causing strengthening of one synapse but inhibiting strengthening of the competing synapse, mediated by M-current manipulation in cell culture preparation of rat hippocampal cells

Aim 2: To manipulate M-current activation at network level to endogenously block initiation and spread of epileptiform waveform in slice culture of rat hippocampus, by disallowing mass strengthening of connections. (old aim: study epileptic rat models with enhanced M-current activation (genetically inhibit natural m-current suppression – knockout for M1 receptor?) and test alive animals for tolerance to induction of hippocampal seizure.)

Aim 3: To affect similar suppression of epileptic spread in rat models with enhanced M-current (old aim: study effects of serotonin and/or cholinergic manipulation in enhanced M-current rats and control rats to see if threshold can be rescued) [ Experimental details have not been formulated yet.]

Background and Rationale

A central hypothesis in epilepsy research is that abnormal neuronal activity in certain vulnerable circuits can trigger synaptic and/or circuit modifications that permanently enhance neuronal excitability  epileptogenesis

More than 30 animal models associated with an epileptic phenotype result from spontaneous or induced gene mutations, approximately a third of which encode channel or receptor proteins. (Puranam). Being a multigenic disorder which is sometimes symptomatic, but often idiopathic, a line of treatment worth pursuing is the prevention of the spread of epileptiform activity among the neuronal circuitry of the brain.

Activity induced epileptogenesis: Abnormal discharge in one area  intense synaptic activation in another area  recruitment of more and more neurons into abnormal discharge patterns.

Activity induced synaptic changes bring to mind the area of research in LTP: broadly, the circuitry changes induced by a defined time course of synaptic activity. A transition from labile, short-term activity to the more stable, long-term consolidation via new gene expression and protein synthesis.

Epileptic wave patterns have been attractive to experimental scientists and theoreticians alike, as physical phenomenon that thrusts itself to the forefront of normal human consciousness/behavior by a rapid cascade of systematic recruitment, with seemingly innocuous beginnings (the ability of a few to instigate a large population) and employing mechanisms that are at the heart of normal cognitive function. Epilepsy does not impair a person’s cognitive ability (until excessive activity causes cellular damage), per se, but effectively incapacitates it periodically. It is unpredictable, for the most part, and apparently, unstoppable.

“Unstoppable” is not exactly true. There do exist medication. But often they act massively on the region, not specifically. Since most of the culprits in seizure generation are also key players in cognitive functions such as learning and memory, these drugs can have severe side effects. (For example, attempts at seizure control via the NMDA receptor). So, it would be beneficial to be able to target modulation of the circuit of a more specific nature, at a level less globally effecting the normal functioning of the neural population. This could be achieved if activity among certain pathways could be discouraged from spiking, as a result of spiking in other pathways. In other words, a competitive mechanism that encourages activity in one pathway to discourage activity (and consequent potentiation) in a neighboring pathway – thereby thwarting the spread of activity and strengthening of entire populations of synchronously firing neurons.

Such competitive mechanisms have been detected in the auditory cortex(Seki) and the suspected mediator of sequence dependent competition was the M-current. M-currents are slow, non- inactivating hyperpolarizing currents that, when activated, make a cell less likely to fire an action potential. Sequential firing in converging pathways have shown sequence dependent competition, as opposed to simultaneous potentiation, when M-currents were actively suppressed. However, the reason for such a mechanism was not clear, and exploring this area further as a potential regulator of simultaneous potentiation among neighboring neural pathways

Manipulation of the cholinergic M1 (muscarinic) receptor, which is a natural suppressant of the m-current, could enhance the activity dependent suppression of firing probability of neighboring neurons. Another likely candidate is activation of the serotonin receptor 5-HT7, which is widely distributed in the hippocampus(Treatment) ,and is suspected to play a role in generation of epilepsy. Serotonin is an M-current suppressant in hippocampal pyramidal neurons.(Marrion) and anti- depressants such as wellbutrin (Bupropion), anafranil (Clomipramine, a tricyclic) are known to have an effect of the seizure threshold of non-epileptic subjects, while SSRIs known to have possible effect on seizure-prone individuals. The goal of this study is to characterize the effect of M-current suppression and activation on recurrent and synchronous activity in hippocampal neuronal networks. Aim 1: To establish synaptic competition, i.e. near coincident firing causing strengthening of one synapse but inhibiting strengthening of the competing synapse, mediated by M-current manipulation in cell culture preparation of rat hippocampal cells

In magnitude, not very large, but can probably affect the spike-time dependency window in critical periods. Preliminary data: effect of variably timed inhibition shows shunting (?) effect on paired pulse depression in network pathways. (Does this say something about the size of depolarization at the synapse affecting size of synapse potentiation? What about the literature?)

- M-current has shunting effect? - Changes spike-time dependency window? - So, in comparison to a competing synapse with a larger or smaller m-current effect, what would you expect to see? Aim 2: To manipulate M-current activation at network level to endogenously block initiation and spread of epileptiform waveform in slice culture of rat hippocampus, by disallowing mass strengthening of connections.

Now, how does this translate to the hippocampal network?

- Predictions from network epilepsy models - Shift of BCM curve? Aim 3: To affect similar suppression of epileptic spread in rat models with enhanced M-current References (so far)

Marrion NV. Annu Rev Physiol 1997 59: 483-504 Control of M-current

TREATMENTS OF PSYCHIATRIC DISORDERS - 3rd Ed. (2001)

Jobe PC, Dailey JW, Wernicke JF. Crit Rev Neurobiol 1999 13(4): 317-56 A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders

Gill CH, Soffin EM, Hagan JJ and Davies CH. Neuropharmacology 2002 42(1): 82-92 5-HT7 receptors modulate synchronized network activity in rat hippocampus

Puranam RS, McNamara JO. Curr Opin Neurobiol 9:281-7 Seizure disorders in mutant mice: relevance to human epilepsies

Seki K, Kudoh M, Shibuki K. J Physiol. 2001 533(2):503-18 Sequence dependence of post-tetanic potentiation after sequential heterosynaptic stimulation in the rat auditory cortex

Bacon W L, Beck S G. J Pharm Expmtl Therapeutics 2000 294(2) 672-9 5- Hydroxytryptamine(7) receptor activation decreases slow afterhyperpolarization amplitude in CA3 hippocampal pyramidal cells

Engel et al (ed.) International Review of Neurobiology. Associated Press Vol 45 Brain Plasticity and Epilepsy