the ability to analyse and learn new information and , if necessary , modify ongoing behaviour , based on a combination of previous and recent memories , is an important factor for the survival of organisms in an ever - changing world .
creating and managing these memory traces , comprise core functions of the central nervous system , which rely on its ability to engage in synaptic plasticity .
they can be monitored at different levels , ranging from the subcellular to the behavioural . since its discovery in the late 1960s ( andersen and lmo , 1967 ; bliss and lmo , 1973
; see for review : lmo , 2003 ) , long - term potentiation ( ltp ) has been the subject of intense study , using a plethora of induction protocols , species , and various preparations both in vivo and in vitro .
nowadays , ltp , along with long - term depression ( ltd ) , is widely used as a model of synaptic information storage and are believed to represent the processes of learning and memory in neuronal networks ( abraham , 2003 ; bear , 1996 ; bliss and collingridge , 1993 ; kemp and manahan - vaughan , 2007 ; lynch , 2004 ; whitlock et al . ,
synaptic plasticity in the form of ltp , typically results in both functional and structural reorganisation of the synapse , that evolves over time and comprises different phases , namely ltp - induction ( post - tetanic potentiation ) , short - term potentiation , ltp expression ( early ltp ) and maintenance ( late ltp ) ( abraham , 2003 ; bliss and collingridge , 1993 ; frey et al . , 1993 ;
furthermore , each of these phases is characterised by the different involvement of neurotransmitter systems acting via both ionotropic and metabotropic receptors . for the induction phase ,
several lines of evidence underlie the important role of the activation of n - methyl - d - aspartate ( nmda ) receptors , at least for the hippocampal ca1 region and dentate gyrus ( abraham and mason , 1988 ; collingridge et al . , 1983 ;
errington et al . , 1987 ; fox et al . , 2006 ; frey et al . , 1996 ; manahan - vaughan , 1997 ; niewoehner et al . , 2007 ) . for early ltp ,
activation of the metabotropic glutamate receptors ( mglurs ) , particularly group i mglurs , plays a critical role ( aiba et al . , 1994 ; anwyl , 1999 ; manahan - vaughan , 1997 ; manahan - vaughan and braunewell , 2005 ; manahan - vaughan and reymann , 1996 ; manahan - vaughan et al . , 1998 ; richter - levin et al . , 1994 ) .
late - ltp ( maintenance phase ) requires de novo protein synthesis ( frey et al . , 1996 ; krug et al . , 1984
; otani and abraham , 1989 ) and activation of several immediate - early genes and late - response genes ( abraham et al . , 1991 ; brakeman et al . , 1997 ; cole et al . , 1989
additionally , various neuromodulators can either increase or decrease the probability , magnitude and/or longevity of changes in synaptic transmission , hence affecting the outcomes of patterned synaptic activation ( granado et al .
, 2008 ; kemp and manahan - vaughan , 2005 , 2008 ; kulla and manahan - vaughan , 2002 ; lemon and manahan - vaughan , 2006 ; li et al . , 2003 , 2007 ; manahan - vaughan and kulla , 2003 ; swanson - park et al . , 1999 ) .
besides the different relative involvement of neurotransmitter systems , the induction and/or expression of ltp , as a reflection of central synapses to acquire , process and subsequently store new information , depends upon several other factors , including environmental enrichment , various forms of stress , etc .
bruel - jungerman et al . , 2005 ; duffy et al . , 2001 ;
, 1999 ; xu et al . , 1998 ) , which couple the sensory input to a current behavioural state and provide the contextual frame for processing of sensory stimuli .
thus , taking into account the plethora of mechanisms underlying the phenomenon of ltp , it is not surprising that various factors and/or experimental manipulations can markedly affect its different phases .
however , for most forms of ltp , and particularly for electrically induced ltp , the state of the animal ( synaptic and behavioural ) during a short period of time , both during and immediately after tetanisation , appears decisive in determining the persistence of potentiation ( abraham , 2003 ) . in our study
( bikbaev and manahan - vaughan , 2007 ) , we applied high - frequency tetanisation ( hft ) in freely behaving adult rats and monitored field excitatory synaptic potentials ( fepsps ) in parallel with the intrahippocampal electroencephalogram over a period of 24  h. despite the fact that an identical stimulation protocol was employed for all animals , substantial variation in the outcomes of tetanisation was found . in the first group of animals , a robust ltp occurred that
was stable for at least 24  h ( ltp group ) , in the second group short - term potentiation that endured for up to 3  h was induced ( stp group ) , whereas in the third group a failure of potentiation occurred , i.e. no persistent increase in synaptic transmission was seen ( failure group ) . given this range of tetanisation results , we analysed them in the context of the changes in network activity that occurred during and within first 300  s after tetanisation .
oscillatory activity is an integral part of functional neuronal networks , and significant variability in patterns of oscillatory activity can be registered under certain conditions both in vivo and in vitro .
modification of synaptic weights occurs very fast during the activated state of the hippocampus ( buzski , 1996 ) , with entorhinal 
hippocampal network oscillations at theta frequency playing a crucial role in this process ( kamondi et al . , 1998 ) .
particularly in the hippocampus , theta oscillations ( theta rhythm , rhythmic slow activity ) have been proposed to play a role in a wide variety of hippocampal functions ( see for review : buzski , 2005 ) . in rodents , periods of prominent theta oscillations occur during exploratory behaviour and phases of rapid eye movement rem ( sleep ) ; conditions which are generally termed theta - associated behaviour ( bland , 1986 ; buzski , 2002 , 2005 ; vanderwolf , 1969 ) .
these behavioural states , and particularly exploratory behaviour , are characterised by neocortico - hippocampal transfer of new spatial information when acquisition and/or encoding of sensory information should be facilitated , whereas transfer of the information from the hippocampus to neocortex is associated with other patterns , such as sharp waves and ripples ( bragin et al . , 1995 ; buzski , 1996 ; buzski et al . , 2002 ;
gamma oscillatory activity represents another pattern of network activity , which is characteristic for cortical locations , and is proposed to be involved in various cognitive functions ( buzski and chrobak , 1995 ; fell et al .
, 2001 ; fries et al . , 2001 ; gray and singer , 1989 ; hermann et al . , 2004 ; hopfield , 1995 ; lisman , 1999 ; lisman and idiart , 1995 ; montgomery and buzski , 2007 ; singer , 1993 ) . in the hippocampus of freely moving animals ,
the amplitude of gamma oscillations is higher in the dentate gyrus than in other hippocampal regions expressing gamma oscillations ( bragin et al . , 1995 ) , and
hence , hippocampal theta and gamma oscillations comprise functionally - associated patterns of network activity that emerge as a consequence of the combination of intrinsic oscillatory properties of principal cells and interneurons , the rhythmic activation of which is driven by intra- and extrahippocampal connections ( bartos et al . , 2007 ; bragin et al . , 1995 ; csicsvari et al
. , 2003 ; klausberger et al . , 2003 ; penttonen et al . , 1998 ;
the results of our study demonstrated that the successful potentiation of synaptic transmission ( ltp and stp groups ) in freely moving rats , was preceded by a higher relative theta power in the period of 300  s after hft , when compared with the pre - tetanisation period ( figure 1 ) .
in contrast , a gradual recovery of theta power to pre - tetanisation values , but not an increase , was found in the ltp - failure group . in other words , successful induction of potentiation ( either in the form of stp or ltp ) , resulted in an enhancement of theta oscillatory activity after tetanisation , whereas no such enhancement occurred in rats that showed failure of ltp .
the mean amplitude of a single theta cycle was also significantly higher within the post - tetanisation period in the ltp and stp groups , when compared to the group of failed synaptic potentiation .
taken together , these data suggest that a transient increase of theta power is necessary for the proper handling of sensory input activation ( mimicked here by hft ) .
this , in turn , may play a permissive role in ltp induction , and , in general , in the formation of memory trace(s ) of newly acquired information .
transient enhancement of theta and gamma power in the post - tetanisation period correlates with potentiation of synaptic transmission in the dentate gyrus of freely moving rats .
( a ) examples of eeg epochs , which comprise 100  s long periods of tetanisation ( 200  hz , 10 trains : first train is marked by arrow ) and following 300  s , recorded in rats that showed either ltp ( left panel ) , stp ( middle panel ) or failure of potentiation ( right panel ) , respectively .
asterisk denotes the period immediately after hft , when the amplitude of network oscillations is higher in ltp and stp cases , in comparison with failed potentiation .
scale bar : 20  s. ( b ) successful potentiation ( ltp and stp ) of synaptic transmission is associated with a prominent increase of the relative theta and gamma power particularly in the period encompassing 100  s after tetanisation .
the results were pooled for ltp , stp and failure groups and presented as mean    s.e.m .
( modified from bikbaev and manahan - vaughan , 2007 ) . however , the differences between ltp , stp and failed potentiation groups were not limited in our study by theta oscillations .
we found that within the first 100  s after hft the increase in theta power , and the mean amplitude of a single theta cycle , was accompanied by higher gamma power in the ltp group , and higher amplitude of gamma oscillations within a single theta cycle in both the ltp and stp groups , when compared with cases of failed potentiation ( figure 1b ) .
this indicates that not the increase of theta power per se , but a correlated increase of both theta and gamma power is important for enabling or mediating the plastic changes in synaptic weights .
furthermore , our results show that these enhancements of oscillatory activity should take place within a relatively short period of time for synaptic plasticity to occur . taking into account that the amplitude of gamma oscillations in the dentate gyrus , but not in the ca3 or ca1 regions , is significantly higher in the presence of theta oscillations than in non - theta states ( csicsvari et al . , 2003 )
, these findings suggest that the tetanisation - induced facilitation of theta activity can play a causal role for the enhancement of gamma oscillations . in the dentate gyrus of the intact brain ,
the power of both theta and gamma activity is driven by and strongly depends upon entorhinal input , and is higher during exploratory behaviour ( bragin et al . , 1995 ; csicsvari et al . , 2003 ) .
furthermore , behavioural data indicating enhanced eyeblink conditioning in rabbits that received pairings of stimuli during epochs of prominent theta activity , when compared to those stimulated during non - theta periods ( seager et al . , 2002 ) , provide additional support for a facilitatory role of theta oscillations in learning .
however , one should emphasise that the increase of theta power occurred in our study in the period after tetanisation .
thus , the differences in theta power that we observed , did not comprise an endogenous pre - condition for synaptic plasticity , but rather occurred as a consequence of perforant path stimulation . accordingly ,
if natural theta rhythm is necessary for the acquisition or processing of sensory stimuli , one can presume that the artificial activation of sensory inputs ( in the form of hft ) would require and/or induce an enhancement of oscillatory activity in the theta frequency range , in order to temporally organise neuronal activity and favour synaptic plasticity .
the depolarisation of dendritic compartments of dentate gyrus granule cells via activation of nmda receptors and mglurs , after strong activation of the glutamatergic perforant path , is likely to contribute to such an enhancement .
perforant path stimulation of the dentate gyrus , in conjunction with subsequent firing of mossy fiber collaterals , will also activate parvalbumin - expressing basket cells ( kneisler and dingledine , 1995 ) , which via ionotropic -amino - butyric acid ( gabaa ) receptors provide rhythmic inhibition of somata and perisomatic region of principal cells and play a pivotal role in the generation of both theta ( buzski , 2002 ; klausberger et al .
1995 ) and gamma ( bartos et al . , 2001 , 2007 ; penttonen et al . , 1998 ; vida et al . ,
additionally , activation of gabaa receptors has been reported to be critical also for the generation of transient tetanically induced gamma oscillations in vitro ( traub et al . , 2004 ;
hence , the combination of nmdar - induced dendritic excitation and gabaar - mediated somatic inhibition results in current flow through distal dendrites , which is important for the generation and maintenance of extracellular theta currents ( buzski , 2002 ) .
this could also effectively trigger and/or enhance theta oscillations in post - hft period . in turn
, theta oscillations may dynamically modulate the probability of nmdar activation , which is highest on the peak of the theta cycle and the lowest on the trough ( vertes , 2005 ) .
the increase of gamma power in the post - tetanisation period may rely on the activation of group i mglurs , which was reported to induce gabaar - dependent gamma oscillations in vitro ( whittington et al . ,
we have found recently that prolonged inhibition of mglur5 results in a significant impairment of ltp associated with a marked suppression of gamma oscillations in the dentate gyrus of freely moving rats ( bikbaev et al . , 2008 ) . taken together , correlated activation of granule cells and interneurons , via fast and slow glutamatergic excitation , not only can contribute to long - term synaptic potentiation , but , complemented with fast rhythmic gabaergic inhibition , can affect network oscillations on both short- and long - term time - scales ( figure 2 ) . in this respect , pharmacological modulation of selected neurotransmitter systems , including
the glutamatergic , gabaergic and cholinergic systems , coupled with correlation analysis of network activity and long - term changes in synaptic transmission , would be necessary for a more conclusive support of this suggestion .
for instance , such analysis after activation of the cholinergic system , which can facilitate oscillatory activity in the theta frequency band , and simultaneous inhibition of gabaar- and/or mglur - mediated signalling , which affects hippocampal gamma activity , could help to dissect the roles of theta and gamma oscillations in the shaping of synaptic plasticity . a schematic representation of the consequences of high - frequency tetanisation that occur on the network and cellular levels , and lead towards long - term potentiation of synaptic transmission .
( a ) strong afferent stimulation results in an enhancement of both theta and gamma oscillations , which occurs within 5  min interval after tetanisation and can be mediated via gabars , nmdars and mglurs .
( b ) tetanisation - triggered activation of both ionotropic and metabotropic glutamate receptors is followed by the expression of plasticity - related immediate - early genes ( iegs ) and protein synthesis , which can underlie structural synaptic reorganisation and long - term increase in synaptic efficacy .
experimental procedures that inhibit the induction , expression or maintenance of ltp can result in impairment of post - tetanic potentiation , stp , early ltp or late ltp ( 14 , respectively ) .
grey arrows denote possible links between nmdar and mglur activation and facilitation of network activity in theta and gamma frequency bands .
the apparent relationship between theta activity and certain types of behaviour , and the relative regularity and stability of this oscillatory pattern suggests that theta rhythm may serve as an internal timing mechanism for individual elements of spatially distributed neuronal ensembles ( buzski , 2005 ) . in other words ,
enhanced theta oscillations may provide an appropriate time - window for the firing of individual neurons within currently activated ensemble(s ) and , therefore , optimise the encoding of the acquired signal .
indeed , the firing rate of both principal cells and several classes of interneurons in the hippocampus has been found to be theta phase - locked , i.e. to depend upon the phase of the ongoing theta cycle ( csicsvari et al . , 1999 ;
an important link between hippocampal theta oscillations and the probability of potentiation of synaptic transmission is provided by observations with regard to increases or decreases of synaptic efficacy , which were caused by trains of high - frequency stimulation delivered either at the peak or the trough of theta cycle , and which resulted in ltp or ltd respectively ( huerta and lisman , 1993 , 1995 ; mccartney et al .
, 2004 ; pavlides et al . , 1988 ) . during naturally occurring , locomotion - induced theta oscillations , ltp , that persists for at least 48  h , is preferentially induced by stimuli delivered near the local theta peak in behaving animals ( hyman et al . , 2003 ;
orr et al . , 2001 ) , whereas in anesthetised animals a long - lasting enhancement of fepsp is elicited , if hippocampal afferents are stimulated synchronously on the peak of theta oscillations ( hlscher et al . , 1997 ; pavlides et al . , 1988 )
this demonstrates that not only the parameters of the stimulation protocol , but also the timing of tetanisation relative to the phase of theta cycle , can change the direction of synaptic plasticity ( ltd vs. ltp ) .
thus , tetanisation - driven increases of theta and gamma oscillations , such as those observed in our study ( bikbaev and manahan - vaughan , 2007 ) , seem to be intrinsically interconnected , and play complementary roles in synaptic potentiation .
the heightened theta power in the period after tetanisation is likely to temporally organise the firing of principal cells within theta time - windows , hence supporting the increase of the amplitude of gamma oscillations .
bearing in mind that the higher amplitude of gamma oscillations reflects a higher degree of synchronisation in the network ( see for review : axmacher et al . , 2006 ) , the increase of gamma power in the period immediately after tetanisation may indicate that , during the facilitated theta activity , the firing of principal cells and interneurons is more synchronised ( or precise ) and/or recruits more elements into the network activity .
accordingly , enhanced gamma oscillations synchronise neuronal firing within narrower gamma time windows and elevate the probability for afferent stimuli to coincide with the peak of theta cycle , where the gamma amplitude is highest , hence resulting in the strengthening of the activated synaptic pathway .
the outcomes of studies of spike - timing dependent plasticity ( see for review : dan and poo , 2004 ) demonstrate that such synchronisation of neuronal spiking , within a 1030  ms window : which precisely matches to a single gamma cycle , can dramatically increase the probability of potentiation of activated synaptic connections .
moreover , in in vitro recordings from the primary visual cortex , where theta activity is generally not so prominent as in the hippocampus , pairing the stimuli with either the peak or trough of oscillations in the beta and gamma frequency ranges has been found to effectively drive synaptic plasticity towards potentiation or depression , respectively ( wespatat et al . , 2004 ) . in this context , one can conclude that the transient enhancement of theta and gamma oscillations in the post - tetanisation period reflects the engagement of the system in encoding of acquired information .
this can result in a subsequent  reconfiguration  of the network , coupled with the strengthening of currently activated connections , and the weakening of the others .
furthermore , facilitated theta activity can support a tighter timing control of the firing of principal cells and interneurons in the network , which serves to optimise information processing .
tetanisation - triggered enhancement of gamma oscillations is associated , on the other hand , with higher synchronisation and reflects the coordinated ensemble activity aimed to encode / retrieve relevant memories .
accordingly , the absence or inconsistency of such changes in network activity can be related to the lack , or insufficiency , of activation of required neurotransmitter systems , sub - optimal conditions for the processing of sensory information and , therefore , a lower probability for ltp .
for several decades , theta rhythm was regarded in rodents as an electrographic hallmark of exploratory behaviour , that occurs when the hippocampus is engaged in the acquisition and processing of sensory stimuli , which can lead in turn to experience - based modification of ongoing behaviour .
gamma oscillations were also proposed to play a role in various cognitive processes both in human and animals . at the neuronal level ,
the acquisition and formation of memory traces are believed to rely on activity - related changes in synaptic efficacy , and ltp of synaptic transmission after patterned afferent stimulation is considered as an adequate experimental model of these processes . however , despite the existence of extensive experimental data showing the involvement of hippocampal theta and gamma oscillations in cognitive processes , a relationship between the coordinated enhancement of both theta and gamma power immediately after tetanisation and the consequences of induction of synaptic plasticity in freely moving rats was not , to our knowledge , described earlier .
we found that changes in theta and gamma oscillatory activity precede electrically induced potentiation of synaptic transmission .
importantly , the correlated tetanisation - driven enhancement of both theta and gamma oscillations is associated with successful short- and ltp , but not with its failure .
these findings link ltp with the oscillatory activity of rather large assemblies of hippocampal principal cells and interneurons , and provide additional support for the role of hippocampal theta and gamma oscillations in information processing and the formation of new memories .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
 in the hippocampus in vivo , both synaptic plasticity and network activity are closely interdependent . 
 we have found that immediately after an attempt to induce long - term potentiation ( ltp ) , changes in theta ( 510  hz ) and gamma ( 30100  hz ) activity correlate tightly with the occurrence of ltp , suggesting that tetanisation - driven activation of sensory inputs synchronises the activity of granule cells and interneurons , and thus , facilitates the encoding of acquired stimuli . 
 this results in increase of theta and gamma power , and elevates the probability that afferent stimuli both coincide with the peak of theta cycle and reach their post - synaptic target within the gamma time - window ( of 1030  ms ) . 
 both these mechanisms can effectively shift the direction , of tetanisation - induced changes in synaptic weight , towards potentiation and induction of ltp . here , we discuss our findings in the context of possible mechanisms that link theta and gamma oscillations with ltp induction , as well as their role in information processing and formation of memories . 
Long-Term Potentiation of Synaptic Transmission as a Model of Synaptic Plasticity
Tetanisation-Triggered Facilitation of Theta and Gamma Activity Favours LTP
The Direction of Change in Synaptic Weight Correlates with the Phase of Theta Cycle
Summary
Conflict of Interest Statement